VISION PAN-AMERICA THE PAN-AMERICAN JOURNAL OF OPHTHALMOLOGY
ISSN 2219-4665 Vol. 13(3), SUPPLEMENT.
Defining Best Practice Standards for the Diagnosis and Management of Diabetic Retinopathy and Diabetic Macular Edema in Latin America Definición de estándares de buenas prácticas para el diagnóstico y tratamiento de la retinopatía diabética y el edema macular diabético en América Latina Definição dos padrões de boas práticas para o diagnóstico e tratamento da retinopatia diabética e do edema macular diabético na América Latina
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Defining the standard of care in Medical Retina LUCENTIS® for treatment of: ➟ Wet age related macular degeneration. ➟ Visual impairment due to diabetic macular edema. ➟ Visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO). ➟ Visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Note: Before prescribing, consult full prescribing information. Presentation: Vial: Ranibizumab. Each vial contains 2.3 mg of ranibizumab in 0.23 mL solution. Pre-filled syringe: Ranibizumab. Each pre-filled syringe contains 1.65 mg of ranibizumab in 0.165 mL solution. Indications: ◆ Treatment of neovascular (wet) age-related macular degeneration (AMD) ◆ Treatment of visual impairment due to diabetic macular edema (DME) ◆ Treatment of visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO) ◆ Treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM) ◆ Dosage: ◆ The recommended dose is 0.5 mg (0.05 mL) given as a single intravitreal injection. The interval between two doses should not be shorter than 1 month. AMD, DME, RVO: ◆ Patients should be monitored monthly for visual acuity ◆ Treatment is given monthly and continued until maximum visual acuity is achieved, confirmed by stable visual acuity for three consecutive monthly assessments performed while on Lucentis® treatment. Treatment is resumed with monthly injections when monitoring indicates a loss of visual acuity due to wet AMD, DME or macular edema secondary to RVO and continued until stable visual acuity is reached again for three consecutive monthly assessments ◆ Lucentis and laser photocoagulation in DME or in branch RVO: Lucentis has been used concomitantly with laser photocoagulation in clinical studies. When given on the same day, Lucentis should be administered at least 30 minutes after laser photocoagulation. Lucentis can be administered in patients who have received previous laser photocoagulation. CNV secondary to PM: Treatment is initiated with a single injection, further treatment is recommended if monitoring reveals signs of disease activity ◆ The frequency of monitoring should be determined by the treating physician ◆ Lucentis must be administered by a qualified ophthalmologist using aseptic techniques. Broad-spectrum topical microbicide and anaesthetic should be administered prior to the injection ◆ Not recommended in children and adolescents ◆ Contraindications: Hypersensitivity to ranibizumab or to any of the excipients, patients with active or suspected ocular or periocular infections, patients with active intraocular inflammation ◆ Warnings/Precautions: ◆ Intravitreous injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Therefore proper aseptic injection techniques must be used. Patients should be monitored during the week following the injection to permit early treatment if an infection occurs ◆ Transient increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of Lucentis. Sustained IOP increases have also been reported. Intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately ◆ There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A numerically higher stroke rate was observed in patients treated with ranibizumab 0.5 mg compared to ranibizumab 0.3 mg or control, however, the differences were not statistically significant. Patients with known risk factors for stroke, including history of prior stroke or transient ischemic attack
should be carefully evaluated by their physicians as to whether Lucentis treatment is appropriate and the benefit outweighs the potential risk ◆ Available data do not suggest an increased risk of systemic adverse events with bilateral treatment ◆ As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis ◆ Lucentis has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole ◆ There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischemic visual function loss, treatment is not recommended ◆ Should not be used during pregnancy unless the expected benefit outweighs the potential risk to the fetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child; use of effective contraception recommended for women of child-bearing potential; breast-feeding not recommended ◆ Following treatment patients may develop transient visual disturbances that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist ◆ Interactions: No formal interaction studies have been performed ◆ Adverse reactions: ◆ Very common adverse reactions are: intraocular inflammation, vitritis, vitreous detachment, retinal hemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival hemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperemia, eye pruritus, intraocular pressure increased, nasopharyngitis, headache, arthralgia ◆ Common adverse reactions are: retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous hemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site hemorrhage, eye hemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid edema, eyelid pain, conjunctival hyperemia, stroke, influenza, urinary tract infection*, anemia, anxiety, cough, nausea, allergic reactions (rash, pruritus, urticaria, erythema) ◆ Uncommon adverse reactions are: blindness, endophthalmitis, hypopyon, hyphema, keratopathy, iris adhesions, corneal deposits, corneal edema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation ◆ Serious adverse events related to intravitreal injections included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. * observed only in the DME population Packs and prices: Country specific. Legal classification: Country specific.
Please find the full prescibing information in the Novartis booth
Lucentis Indications may vary from country to country. Physicians should refer to their National Prescribing Information. Novartis Pharma AG CH-4002 Basel, Switzerland
©2014 Novartis Pharma AG
May 2014
GLO/LUC/0117
Defining Best Practice Standards for the Diagnosis and Management of Diabetic Retinopathy and Diabetic Macular Edema in Latin America Schlottmann P.1, Acosta C.2, Alezzandrini A.A.3, Bafalluy J.4, Biccas L.5, Hidalgo Cano6, Damico F.M.7, Dib G.8, Fromow-Guerra J.6, Jorge R.9, Lavinsky D.10, Morales-Canton V.11, Roca J.A.12, Farah *M.E.13
Abstract Purpose: To provide evidence-based recommendations and guidance for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) based on recently published clinical evidence and clinical experience. Methods: A literature search using PubMed and the Cochrane Library was performed with the terms “diabetic macular edema” or “diabetic retinopathy” to identify studies published from January 2008 to November 2013. This was followed by a manual search of references cited in selected papers published in peer-reviewed journals. The references identified in these literature searches were reviewed and presented by members of the Latin America DME expert panel to the entire group during the 2-day consensus meeting. During this meeting, the experts formulated recommendations with consideration of the health benefits, risks, and adverse effects of interventions. References used to support recommendations were assigned a level of evidence based on the Strength of Recommendation Taxonomy (SORT) evidence rating system. Results: Thirty-one consensus recommendations were formulated. These include the recommendation for early glycemic control in diabetic patients in order to reduce the risk of progression of ocular disease. The expert panel also recommended the collection of epidemiological data to further define the prevalence of DR and DME in Latin America and to establish management and treatment algorithms for various stages of the disease. The need for early screening and development of infrastructure to ensure appropriate followup and treatment of those in need is further emphasized. Both fluorescein angiography
(FA) and optical coherence tomography (OCT) are needed for proper assessment of disease progression and response to therapy. Based on available high-level evidence, we recommend ranibizumab as the gold standard for the treatment of DME and panretinal photocoagulation (PRP) as the gold standard for proliferative DR. Vitrectomy should be considered in the presence of macular traction or if edema is not responding to pharmacological therapy. As intravitreal steroids provide a reduction in edema, they can be used to ameliorate the effects of other therapies as well as in pseudophakic eyes. Finally, when selecting a therapy for DR and/or DME, it is of particular importance to consider the general health status of a patient. Conclusion: Although these guidelines are not intended to be a replacement for clinical judgment, they should help to streamline the management of DME across Latin America and ensure that patients receive the best available care in a timely manner. Introduction The purpose of this document is to provide guidance to Latin American ophthalmologists and retina specialists regarding the diagnosis and management of diabetic retinopathy (DR) and diabetic macular edema (DME). The outlined recommendations were systematically developed based on a thorough consideration of the medical literature and clinical experience. However, these guidelines are not intended to be a replacement for clinical judgment, but rather to inform patterns of practice. Furthermore, this document cannot be used as a legal resource, as it cannot provide individualized guidance for all patients in all situations. In fact, when considering therapeutic approaches for diabetic patients with ocular involvement, ophthalmologists must consider the needs,
Organizacion Medica de Investigación, Buenos Aires, Argentina. 2Universidad CES, Medellín, Colombia, 3Universidad de Buenos Aires, Argentina, 4Universidad Nacional de Rosario, Rosario, Argentina, 5Clinica Ocular Oftalmología, Vítoria, Brazil, 6Universidad Nacional Autónoma de México, México City, México, 7Universidade de São Paulo, Brazil, 8Universidad del Zulia, Maracaibo, Venezuela, 9Universidade de São Paulo, Ribeirao Preto, Brazil, 10Universidade Federal Rio Grande do Sul, 11Asociación para Evitar la Ceguera en México, México City, México, 12Universidad Peruana Cayetano Heredia, 13 Universidade Federal São Paulo, Brazil. 1
*Address for correspondence: M.E. Farah, mefarah@uol.com.br
BEST PRACTICE STANDARDS IN DR AND DME
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preferences, values, as well as financial and personal context for each individual patient, and work within the realities of their healthcare setting. It is understood that there are imbalances in human, financial, and healthcare resources across Latin American countries and regions and that these factors may affect clinician and patient preferences, options, and decisions. Methods An English-language literature search using PubMed and the Cochrane Library was performed with the terms “diabetic macular edema” or “diabetic retinopathy” to identify studies published from January 2008 to November 2013. This was followed by a manual search of references cited in selected papers published in peer-reviewed journals. Meta-analyses, systematic reviews, and randomized clinical trials with at least 1 year of follow-up published in the past 5 years were preferred sources. References identified by the literature searchers were reviewed by members of the Latin America DME expert panel – with each member reviewing the references that pertained to his/her respective topic – to ensure they were relevant and of acceptable methodological quality. The expert panel members also presented key evidence to the entire group during a 2-day consensus meeting that took place on
November 13-14, 2013, in Miami, Florida. During this meeting, the experts reviewed the evidence and formulated recommendations with consideration of the health benefits, risks, and adverse effects of interventions. References used to support recommendations were assigned a level of evidence based on the Strength of Recommendation Taxonomy (SORT) evidence rating system (Appendix 1). In the absence of direct evidence, recommendations were written to reflect the unanimous consensus of the expert panel. The guidelines highlight key points from the data in two ways: intead of. 1. “To consider”: points are key extrapolations from the data and daily clinical practice that are deemed important but for which the published evidence is not as strong. Thus, they are not assigned an evidence-based weighting. 2. “Consensus”: recommendations are evidence-based statements regarding patient management and are supported by the cited literature. Current Reality of Diabetes Mellitus Diabetes mellitus (DM) includes a group of metabolic diseases in which the pancreas does not produce sufficient insulin, or cells do not respond to the insulin that is produced.1 The disease is characterized by symptoms of polyuria (frequent urination), polydipsia
(increased thirst), and polyphagia (increased hunger). Untreated DM can lead to numerous macro- and microvascular complications including DR and DME.2 The landmark Diabetes Control and Complications Trial (DCCT)3 and its sequel, the Epidemiology of Diabetes Interventions and Complications (EDIC) study,4 established that intensive glycemic control reduces both macroand microvascular complications of the disease in patients with type 1 DM, including the reduction in the risk of developing progressive retinopathy. Furthermore, in both trials, the benefits of intensive therapy were sustained over a prolonged period of time.5-8 However, one must also keep in mind that, in addition to insulin, glucose regulation involves other hormones and multiple organ systems.9 Furthermore, insulin replacement does not fully mimic the actions of insulin secreted by the pancreas. This could be a potential explanation for some of the adverse events observed with intensive insulin therapy; ie, 3-fold increase in severe hypoglycemia, 3-fold increase in seizures and coma, and increase in weight gain.10 The United Kingdom Prospective Diabetes Study (UKPDS) assessed the role of intensive glycemic control in over 5 000 patients with type 2 DM.11 In summary, the
Appendix 1. Assessing Quality of Evidence – Strength of Recommendation Taxonomy (SORT)
Study quality
Diagnosis
Level 1: Good quality • patient-oriented evidence •
• Level 2: Limited quality • patient-oriented evidence •
•
Treatment/prevention/ screening
Validated clinical decision rule SR/meta-analysis of high-quality studies High-quality diagnostic cohort study*
•
Unvalidated clinical decision rule SR/meta-analysis of lower quality studies or studies with inconsistent findings Lower-quality diagnostic cohort study or diagnostic case-control study
•
• •
• • •
Prognosis
SR/meta-analysis or RCTs with consistent findings High-quality individual RCT† All-or-none study‡
•
SR/meta-analysis of lower quality clinical trials or of studies with inconsistent findings Lower quality clinical trial Cohort study Case-control study
•
•
•
• •
SR/meta-analysis of good quality cohort studies Prospective cohort study with good follow-up
SR/meta-analysis of lower quality cohort studies or with inconsistent results Retrospective cohort study or prospective cohort study with poor follow-up Case-control study Case series
Level 3: other evidence Consensus guidelines, extrapolations from bench research, usual practice, opinion, disease-oriented
evidence (intermediate or physiologic outcomes only), or case series for studies of diagnosis, treatment, prevention, or screening * High-quality diagnostic cohort study: cohort design, adequate size, adequate spectrum of patients, blinding, and a consistent, well-defined reference standard. † High-quality RCT: allocation concealed, blinding if possible, intention-to-treat analysis, adequate statistical power, adequate follow-up (greater than 80 percent). ‡ In an all-or-none study, the treatment causes a dramatic change in outcomes, such as antibiotics for meningitis or surgery for appendicitis, which precludes study in a controlled trial. 4
BEST PRACTICE STANDARDS IN DR AND DME
SR = systematic review; RCT = randomized, controlled trial Used and adapted with permission from: Ebell MH, Siwek J, Weiss BD, Woolf SH, Susman J, Ewigman B, Bowman M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):548-556.
trial has shown that intensive glycemic and blood pressure control reduce the risk of diabetic complications. The greatest effects of tight glucose control were in reduction of microvascular complications. There were no major differences between pharmacological therapies. Finally, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial assessed the impact of intensive glycemic, lipid, and blood pressure control on Cardiovascular Disease (CVD) related outcomes in over 10 000 patients with type 2 DM and established risk factors (ie, previous cardiovascular event, smoking, etc.).12,13 Although intensive glycemic and dyslipidemia control reduced the rate of progression of DR, it increased the risk of death in patients with high risk for CVD.13,14 To consider • The trials did not include Latin American populations; thus, the data needs to be extrapolated. • Intensive glycemic therapy might be associated with a brief period of worsening of ocular disease in some patients, mainly during the first 2 years. In order to rapidly control DR progression and its visionthreatening complications secondary to this unexplained natural progression of the disease, ophthalmologists and retina specialists should ensure more frequent follow-up and potentially more aggressive treatment during this initial period. Consensus recommendations 1. Early and intensive glycemic control in diabetic patients is necessary as it reduces the risk of progression of DR and DME in patients who are not at high risk for CVD events. [Level 1 5,7,14] 2. Ophthalmologists and retina specialists need to ensure that their diabetic patients are also followed and managed by diabetes specialists to ensure optimal therapeutic outcomes. [Level 3/Consensus] Epidemiology of DME and Burden of Disease According to data published in 2013 by the International Diabetes Federation, approximately 382 million people suffer from DM worldwide.15 It is also projected that this number will increase to 592 million by the year 2035. DR and DME are highly prevalent and debilitating eye-related microvascular complications of DM.16 While DR is present in 35% of diabetic patients, approximately 8% develop the
Algorithm I Screeninga for Diabetic Retinopathy
Type 1 Diabetes Diagnosed After Puberty
Type 1 Diabetes Diagnosed Before Puberty
Screening should be initiated 5 years following the diagnosis of diabetes
Screening should be initiated at puberty (Unless there are other considerations that would suggest the need for an earlier exam)
Type 2 Diabetes
Screening should be initiated at the time of diagnosis
Presence of NonProliferative Retinopathy Mild
Moderate
Severe
Annual Examination
Follow-up every 6 months
Follow-up every 3 months
Presence of Proliferative Retinopathy YES Mild annual examination
NO Moderate or severe examination every 3-6 months
Annual examination for all diabetes types
The algorithms are used with permission from Canadian DME treatment algorithms (Hooper P, et al. Ophthalmologica. 2014;231(1):2-15). The algorithms are further modified with permission to reflect current practice and requirement in Latin American countries. Screening evaluation should include: 1. Measurement of visual acuity; 2. Intraocular pressure; 3. OCT to assess the presence of macular edema; 4. Biomicroscopy to assess the presence of neovascularization of the iris and angle; 5. Fundus photos to document, stage, and compare the progression of the disease.
a
proliferative form of the disease.16 DME, defined as retinal thickening within two disc diameters of the foveal center, can occur at any stage of the disease.17 Its severity ranges from mild and asymptomatic to profound loss of vision.18 It is estimated that 13% to 25% of patients with DM develop DME over the course of 10 years,19 with the highest risk among type 2 DM patients who use insulin.20 The prevalence of DME also varies with the stage of DR, from 3% in those with mild, nonproliferative disease to 71% in patients with a more proliferative form.18 DME and clinically significant DME (CSDME) appear to be more prevalent in black and Hispanic populations compared to Chinese or Caucasian individuals.21-23 The prevalence of CSDME in the type 2 DM population in South America varies between 3.4% and 5.5%.24 Contributing factors include changes in dietary habits and increasingly sedentary lifestyle.25 According to the Los Angeles Latino Eye Study, 37.4% of diabetics in Latin America have DR and 10.7% have DME.26 Both DR and DME have negative consequences on quality of life and carry a significant economic burden on the patient, family members, society, and health care system.27,28 In regard to natural history, the ocular disease progresses from retinal thickening to centerinvolving disease and finally to deterioration
in visual acuity (VA). If untreated, 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters are lost over 3 years and the overall prognosis is poor.17 This underlines the need for early screening, detection, and treatment.29,30 Algorithm 1 presents the recommendations regarding screening for nonproliferative and proliferative DR. As teleophthalmology is restricted to the diagnosis of eye disease, it is beneficial only in areas where subsequent treatment can be offered.31 In order to improve management and reduce the impact of diabetic eye disease on patients, the economy, and healthcare systems, public awareness programs and epidemiological studies are needed.16,32 Future research is necessary to better understand the potential role of risk factors and genetic predisposition to shape public health programs. To consider • Lack of awareness about DM and its consequences presents a significant problem in Latin America. About half of diabetics in Latin America are unaware that they have the disease and are first entered into medical systems when they note changes in their vision. • Both genetic and lifestyle factors contribute to the increasing prevalence of DM, DR, and DME in Latin America.
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Algorithm II Treatment of Proliferative Retinopathy In some instancesb, it is beneficial to treat patients prior to development of high risk criteria Diabetic Retinopathy Study High-risk Characteristics Patient lives far from the clinic; evidence of rapidly progressing disease, questionable compliance, patients with type 2 diabetes, or older patients.
b
The presence of any 3 of the following: • Neovascularization • NVD • Severity of neovascularization • NVD > ¼ disc area in size • NVE > ½ disc area in size •Preretinal or vitreous hemorrhage Evidence of Central Macular Edema YES
Stay away from any area of traction during PRP. PRP may be associated with risk of fibrosis. Caution is required. c As per ETDRS criteria
PRPc+ Anti-VEGF
NO
PRPc
Perform Post-PRP Follow-up after 3 Months Vessels are Growing and/or Appear Active
Presence of Hemorrhage (Visually significant or non-clearing)
Augment PRP
Anti-VEGF
Progressive PDR after Maximal PRP
NO
Hemorrhage cleared
Vitrectomy
YES
Augment PRP
NVD = NVD, neovascularization of the disc; NVE = neovascularization elsewhere; PRP = panretinal photocoagulation; VEGF = vascular endothelial growth factor; ETDRS = Early Treatment Diabetic Retinopathy Study; PDR = proliferative diabetic retinopathy.
•
•
Current epidemiological studies lack proper definitions of ethnicity. Definition and classification of patients according to their ethnicity is needed to assess genetic predisposition to the development of DR and DME. The shortage of retina specialists is a considerable problem in all Latin American countries.
Consensus recommendations 3.
4.
5.
Each country/region should make an attempt to collect epidemiological data to assess prevalence of DM, DR, and DME. [Level 3/Consensus] The different methods of data collection should be recorded and taken into consideration when interpreting the results of the epidemiological studies. [Level 3/Consensus] DM remains a poorly defined condition from an ophthalmologist’s perspective. Thus, follow-up algorithms for various stages of the disease need to be established. [Level 3/Consensus] In order to be successful and result in improvement in health outcomes, public awareness and screening programs have to be supported by proper infrastructure to ensure follow-up and treatment of those in need. [Level 3/Consensus]
Pathophysiology of DME The exact mechanism by which chronic hyperglycemia causes the development of DR and DME is not completely understood, and is most likely multifactorial. The common pathway begins with the disruption of the inner blood retina barrier (BRB), which allows vasopermeability and movement of water.33,34 Disruption of 6
BEST PRACTICE STANDARDS IN DR AND DME
the inner BRB is a complex process that involves changes in the tight junction, pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, and vitreoretinal traction. Structural and functional changes are noted in neurons and glial tissue in early phases of the disease, long before changes in the vessels are observed.33 Sustained hyperglycemia affects several vasoactive factors including vascular endothelial growth factor (VEGF), protein kinase C (PKC), heparin, angiotensin II, and pigment epithelium derived factor (PEDF).35-38 This leads to increased permeability of the BRB and leakage.39 VEGF, the most studied cytokine involved in the pathogenesis of DME, is produced by many retinal cells.40-46 Hypoxia related to vasoconstriction and capillary loss leads to upregulation of VEGF expression and increased vascular permeability.47,48 It has been suggested that some forms of PKC also play an important role in VEGF-induced vasopermeability.36 Thus, it is not surprising that PKC inhibitors have been shown to significantly reduce VEGF-induced fluorescein leakage.36 Clinical and anatomical evidence also indicates that abnormalities in the vitreoretinal interface may play an important role in the pathogenesis of DME.49 For example, adhesion of vitreous in the macula is related to an increase in macular edema. Accumulation of advanced glycation end products in the vitreous cortex leads to increased adhesion of posterior vitreous to the internal limiting membrane (ILM). To consider • The interactions and the role of various cytokines in the pathogenesis of DR/DME are yet to be fully understood. The fact that 10% of patients in the RIDE and RISE trials50 at 24 months progressed despite complete elimination of VEGF indicates involvement of other pathways. • Differences in pathogenesis of the disease might impact therapeutic decisions. Consensus recommendation 6. Although there are many factors involved in the pathogenesis of DR and DME, the role of VEGF in the pathogenesis of DME is the most understood. As such, VEGF-related signaling is presently the only approved and recommended treatable pathway. [Level 150-57] Imaging Modalities in the Management of DME: Application of the Latest Advances in Daily Practice Role of Normal and Panoramic Angiography in the Diagnosis of DME Fluorescein angiography (FA) has played a pivotal role in the management of DME for over half a century.58,59 As patterns of hyperfluorescence and hypofluorescence provide insight into the pathophysiology of the disease, they are useful in guiding therapeutic decisions.59 Thus, despite recent advances in other imaging techniques, including optical coherence tomography (OCT), FA continues to play a key role in the assessment of therapeutic outcomes.60 One of the limitations of the traditional FA technique is its inability to capture a single image of the entire ocular fundus.61 As standard FA cameras typically capture an image 30° or 50° across, the Diabetic Retinopathy Study developed a protocol consisting of 7 standard 30° images.62 The width of this composite set of images is approximately
75°. However, as diabetic ischemia and capillary nonperfusion occur commonly in the midperiphery,63 these might be missed with traditional angiography. Ultra wide-angle fluorescein imaging techniques capture fundus images up to 200° in breadth, allowing detection of peripheral abnormalities such as peripheral nonperfusion or leakage from peripheral vessels.59,61 This may allow a more targeted and stepwise laser approach that would minimize laser-induced adverse effects such as field loss and macular edema.59 Further exploration of the significance of peripheral retinal signs detected by panoramic angiography is warranted. Role of OCT in the Diagnosis of DME OCT is a noninvasive and noncontact diagnostic method that uses infrared light reflections to produce reliable, reproducible, and objective cross-sectional images of the retinal structures and the vitreoretinal interface.64-67 Since its introduction in the early 1990s, OCT brought new insights about morphological changes of the retina in DM patients and became the most important diagnostic and prognostic tool in the management of DR and DME.68-75 Its role in DME includes the evaluation of retinal thickness, cystoid macular edema, intraretinal exudates, and subretinal fluid.71,72 A systematic literature review comparing OCT with traditional diagnostic tests (stereoscopic fundus photography or biomicroscopy) concluded that OCT performs well in the diagnosis of DME.74 OCT is also important in monitoring the response to treatments, and has been accepted unanimously by the Diabetic Retinopathy Clinical Research Network (DRCR.net) in their studies involving diagnosis, treatment, and follow-up of DME patients.68,75,76 The rapid development and improvement in OCT instrumentation further contributed to the wide use of the technology.68,77 Earlier OCT systems use time-domain (TD) detection in which the reference mirror position and delay are mechanically scanned to sequentially measure signals from different depths and produce axial scans.73,76 More recently, spectral or Fourier domain detection has become commercially available. Spectral domain (SD) OCT uses an interferometer with a high-speed spectrometer to measure light signals from all time delays simultaneously and, as such, provides higher axial image resolutions.78-80 SD-OCT carries several advantages over TD-OCT including improved resolution, improved acquisition speed, and
Table 1. OCT Terminology Standardized by the DRCR.net
Term
Definition
Retinal thickness
The value in microns of the distance between the OCT layers assumed to be the retinal pigment epithelium and the internal limiting membrane
Retinal thickening
The calculated value equal to the thickness minus the population mean for the variable under consideration
Center point
The intersection of the 6 radial scans
Center point thickness
The average of the thickness values for the 6 radial scans at their point of intersection
Central subfield
The circular area of diameter 1 mm centered around the center point
Central subfield mean thickness
The mean value of the 128 thickness values obtained in the central subfield
OCT = optical coherence tomography; DRCR.net = Diabetic Retinopathy Clinical Research Network Browning DJ et al. Ophthalmology 2008;115(8):1366-1371.
reduction of motion artifacts.68,81 However, most ongoing studies are still mandated to collect TD-OCT data, and currently, no large, prospective multicenter clinical trials have been published using SD-OCT. In addition, DCRC.net have standardized terms for the Stratus TD-OCT technology (Table 182). Common OCT patterns in DME include: 1) diffuse retinal thickening (present in almost all eyes with DME); 2) cystoid macular edema (identified in 44% to 47% of eyes with DME); and 3) serous retinal detachment (present in 3% to 31% of eyes with DME).83 Furthermore, the clinical threshold for a change in OCT thickness is generally >11% because variability of OCT measurements of retinal thickness has been shown to be <11% in diabetics, regardless of the presence of DME.84,85 Enhanced depth imaging (EDI) OCT is used to view the choroid.86 This is important as choroidal thickness is closely correlated to the stage of DR, and with the degree or type of DME. Progressive thickening of the choroidal layer with the progression of DR or the development of DME may reflect the concurrent progression of diabetic choroidopathy. Thus, EDI OCT is a noninvasive technology that enables accurate assessment of choroidal vascular changes in diabetic patients. To consider
has the ability to more precisely detect peripheral areas that need to be treated. • Clinical trials that led to the approval of current DME therapies applied TD-OCT as one of the outcome measures. Thus, presently, TD-OCT should be sufficient to make decisions regarding DME treatment. However, TD-OCT depends on operator skills (most clinical trials that employed TD-OCT used reading centers) and there are less operatorrelated errors with SD-OCT.81 • SD-OCT can be used as a prognostic tool as it provides more detail in regard to location and subtype of lesions.81 There are some indications that a thinner choroid might be a marker of higher risk of disease progression. • EDI-OCT is a promising tool, but it is still in exploratory stages. There are some indications that support the relationship of choroidal thickness with the progression of DME. Consensus recommendations 7.
FA remains an important tool to assess the area of leakage and guide therapeutic decisions in patients with DME. [Level 158,60,62]
•
8.
Although it might be useful for the assessment of patients who are not responding to treatment, wide-field FA is unnecessary for proper management of DME patients. [Level 3/Consensus]
9.
Since OCT can objectively measure retinal thickness, it is considered an important tool and should be used in the diagnosis and management of DME. [Level 174,76,82]
•
•
Relationship between peripheral nonperfusion and DME is yet to be established. Panoramic FA is an emerging imaging strategy. It provides more information compared to traditional technique, but it is expensive and time consuming. Panoramic FA might improve effectiveness of laser treatment as it
BEST PRACTICE STANDARDS IN DR AND DME
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Table 2. Diabetic Retinopathy (DR) Disease Severity Scale
Proposed disease severity level
Findings observable on dilated ophthalmoscopy
No apparent retinopathy
No abnormalities
Mild nonproliferative DR
Microaneurysms only
Moderate nonproliferative DR
More than just microaneurysms but less than severe nonproliferative diabetic retinopathy
Severe nonproliferative DR
Any of the following: • 20 intraretinal hemorrhages in each of 4 quadrants • Definite venous beading in 2+ quadrants •
Proliferative DR
Prominent intraretinal microvascular abnormalities in ≥1 quadrants and no signs of proliferative retinopathy
One or more of the following: neovascularization, vitreous/preretinal hemorrhage
Wilkinson CP et al. Ophthalmology 2003;110(9):1677-1682.
Ideally, SD-OCT should be used as it provides greater insight into retinal morphology. [Level 3/Consensus] Classification of DR and DME Classifying the natural progression of DR is critical in clinical decision making and for communication among colleagues and between medical specialties. The original classification of DR was described in the Airlie House Symposium in 1968.87 Since then, several modified classification systems have been developed and integrated into the published guidelines.88-90 These classification systems, used to grade fundus photographs, are based on the comprehension of the natural progression of DR gained from the ETDRS. The ETDRS classification is regarded as the gold standard for use in clinical and epidemiological studies.89 However, the applicability of the ETDRS scoring system in daily clinical practice is limited due to its various levels of severity, complicated grading rules, and the need for correlation with standard retinal images.90 These requirements are often unnecessary in daily practice and patient care. The International Clinical Diabetic Retinopathy Disease Severity Scale, published in 2003, has been adopted by various international clinical guidelines.90 This new international classification incorporates evidence on disease progression from the ETDRS and, according to changes in retina, stratifies DR into 5 levels of severity. These include: 1) no apparent DR; 2) mild nonproliferative DR; 3) moderate nonproliferative DR; 4) severe nonproliferative DR; and 5) proliferative DR (Table 2). The International Clinical Diabetic Macular Edema Disease Severity Scale is also simple to use. The first step is to assess the 8
BEST PRACTICE STANDARDS IN DR AND DME
presence or absence of DME. If DME is present it can be categorized as mild, moderate, or severe (Table 390). These international classification systems have been endorsed by most international authorities, including the World Health Organization, as standard systems for guiding evidence-based practice. While these classifications have not replaced the ETDRS, they have been demonstrated as useful guides for population screening and for facilitating timely treatment. To consider • In regard to DME treatment, it is important to assess whether the edema is diffuse or focal, central or peripheral, and to evaluate proliferation and traction. Future classification of DME should take these characteristics of the disease into consideration. • DME classifications should also include prognosis and the risk of progression, based on which the treating clinicians can schedule appropriate and timely follow-up with their patients. Consensus recommendation 10. The international classifications are more applicable to daily clinical practice, especially the management of DR, than the ETDRS classifications. Thus, they should be used until classifications with new parameters obtained by new diagnostic imaging techniques are available. [Level 3/Consensus] Non-Pharmacological Treatment Modalities Laser Photocoagulation: Strengths and Limitations
History of laser photocoagulation Awareness of the effect of photocoagulation on the eyes dates back to 400 BC when the Greek philosopher Socrates noted that an eclipse burns the retina.91 Inspired by the effects of unprotected viewing of the 1945 solar eclipse on a medical student’s macula, German ophthalmologist Gerhard Meyer-Schwickerath pioneered light coagulation of the retina.92 The first xenon arc-based photocoagulators produced light composed of various wavelengths within the visible and infrared spectrum.93 These instruments lacked precision, required a long duration of exposure, were painful, and resulted in multiple complications. Their application resulted in full thickness retinal burns rather than tissue specific burns.94 The first laser was the ruby laser, invented by Maiman in 1960.91 It was more compact and reliable than its predecessors and was effective in controlling proliferative DR (PDR) in some clinical trials. The introduction of the argon laser in 1968 led to the widespread use of ophthalmic laser photocoagulation.95 The ideal wavelength employed for retinal photocoagulation is characterized by good penetration through ocular media and maximal absorption in the target tissue.91,96 The argon blue-green laser (70% blue 488 nm, 30% green 514.5 nm) was the predominant ophthalmic laser for many years. However, due to several disadvantages, it was later replaced by green and yellow lasers.91,97,98
Key clinical evidence for DR and DME The landmark Diabetic Retinopathy Study (DRS),99 conducted in the mid 1970s, demonstrated a 50% reduction in the risk of severe vision loss in eyes with PDR or severe non-PDR treated with panretinal photocoagulation (PRP) compared to untreated eyes. PRP reduced the risk of severe vision loss (defined as VA of 20/800 or worse at 2 consecutive 4-month visits) caused by complications of PDR from 14.0% to 6.2% during a 2-year period.99,100
The ETDRS was the first randomized, controlled trial to examine laser photocoagulation in the treatment of DME. The study demonstrated a substantially reduced risk of moderate visual loss (~3 ETDRS lines) in patients with clinically significant DME treated with focal photocoagulation.17,101 Analysis of the subgroup with vision worse than 20/40 at baseline demonstrated that 40% of patients improved by ≥6 letters after 3 years.102 Efficacy of focal/grid laser photocoagulation was further confirmed in the DRCR.net trial.103 Over a 2-year period, laser was more effective than intravitreal triamcinolone (1 mg or 4 mg) for most patients with DME; the mean change in the VA letter score from baseline was +1 ± 17 in the laser group, -2 ± 18 in the 1 mg triamcinolone group, and -3 ± 22 in the 4 mg triamcinolone group; P=0.02 for laser vs 1-mg triamcinolone; P=0.002 for laser vs 4-mg triamcinolone). OCT results generally paralleled the VA results. The results of this study established focal/grid photocoagulation as the benchmark against which other treatments are compared in clinical trials of DME.103 However, photocoagulation is also associated with significant adverse effects. To be effective, the ETDRS photocoagulation protocol requires that, in some cases, burns be placed close to the center of the macula. Over time, these burns may develop into areas of progressive atrophy.104 PRP can also cause visual impairments related to the loss of function of burned retinal tissue as well as peripheral visual-field defects, reduced night vision, diminished color vision, and decreased contrast sensitivity.105 It can also contribute to the development or progression of DME, vitreous hemorrhage, and tractional retinal detachment.106,107 In an attempt to reduce these adverse effects, many retina specialists presently use a modified ETDRS technique (mETDRS).108,109 The mETDRS applies burns that are lighter and less intense than those originally specified in the ETDRS protocol.109 However, one must keep in mind that a direct trial comparing ETDRS to mETDRS was never conducted. An alternative approach (mild macular grid [MMG]) that involves the application of mild and widely spaced burns throughout the macula, avoiding the foveal region, was tested against mETDRS.109 At 12 months after treatment, the MMG technique was less effective at reducing OCT-measured retinal thickening than the current mETDRS laser photocoagulation approach. Algorithms II, IV, and V present the recommendations regarding the use of laser in the treatment of DR and DME. The patterned scanning laser (PASCAL) and subthreshold micropulse diode laser are the 2 latest innovations developed to minimize scar formation. So far, these new approaches appear effective, but long-term experience is needed to define their precise roles in DME treatment. The PASCAL (532 nm) photocoagulator, introduced in 2005, applies burns in a rapid predetermined sequence in the form of a multispot pattern array.110 The pulse duration is reduced to 10–30 msec. According to a retrospective, observational case series of 313 patients treated between 2006 and 2008, the pattern scanning laser is comparable to conventional standard laser protocols used for the treatment of vascular retinal disorders.111 Photothermal stimulation can be achieved using a micropulse laser or PASCAL and is designed to target the retinal pigment epithelium with sublethal energy while minimizing the negative thermal effects on the retina. A micropulse diode laser has been shown to be as effective as standard argon laser photocoagulation in reducing DME, while potentially allowing for more frequent administration.112 This new technology has been evaluated in several clinical trials113-115 and case series.116-118 In 2009,
Algorithm III Treatment of Subclinical Macular Edema Diabetic patient with relatively good functional vision (20/25) and OCT evidence of subclinical macular edema (ie, 1 cyst)
Patient complains about diminishing vision and asks about therapeutic options YES
NO
Consider initiating anti-VEGFd
Consider “watch and wait” approach with an assessment after 2 months.d
Clinical judgment is required. Fluorescein angiogram may help in defining the reasons for declining vision. Currently, ranibizumab is the only approved anti-VEGF therapy for DME.
If cysts don’t resolve consider initiating anti-VEGF despite lack of symptom as cysts might damage retina in the long term.
d
Table 3. Diabetic Macular Edema (DME) Disease Severity Scale
Proposed disease severity level
Findings observable on dilated ophthalmoscopy*
DME apparently absent
No apparent retinal thickening or hard exudates in posterior pole
Mild DME
Some retinal thickening or hard exudates in posterior pole but distant from the center of the macula
Moderate DME
Retinal thickening or hard exudates approaching the center of the macula but not involving the center
Severe DME
Retinal thickening or hard exudates involving the center of the macula
* Hard exudates are a sign of current or previous macular edema. DME is defined as retinal thickening, which requires a 3-dimensional assessment that is best performed by a dilated examination using slit-lamp biomicroscopy and/or stereo fundus photography. Used and adapted with permission from Wilkinson CP, et al. Ophthalmology 2003;110(9):1677-1682.
Figueira et al113 compared the efficacy and adverse effects of conventional green and subthreshold micropulse diode laser photocoagulation for clinically significant macular edema. There were no statistically significant differences in best-corrected VA (BCVA), contrast sensitivity, and retinal thickness between the 2 laser modalities at 0, 4, and 12 months. Laser scarring was much less apparent with subthreshold micropulse diode laser compared to conventional green laser. In another prospective, randomized, controlled, double-masked clinical trial, the subthreshold micropulse 810-nm diode laser technique delivered in a high-density manner was superior to the standard mETDRS photocoagulation over at least 1 year of follow-up.25 Furthermore, significantly more eyes gained and significantly fewer eyes lost substantial vision. One must also keep in mind that the standard protocol for titration and energy selection for these new photocoagulation approaches have yet to be developed.
BEST PRACTICE STANDARDS IN DR AND DME
9
recommendations for the use of laser in the management of DME. [Level 3/Consensus]
Algorithm IV Treatment of Clinically Significant Macular Edema without Vitreomacular Traction 1.Retinal thickening at or within 500 μm of the center of the fovea 2.Hard exudates at or within 500 μm of the center of the fovea associated with retinal thickening 3.Retinal thickening 1 disc area in size, 1 disc diameter from the center of the fovea
Phakic
With Central Macular Thickening
Pseudophakic
Consider fluorescein angiogram To assess perfusion and help define the leakage as focal or diffuse Diffuse edema
Consider anti-VEGF
Focal edema
Consider intravitreal steroids If no desirable outcome with anti-VEGF and the patient is at low risk of glaucoma Consider focal laser Long term effects of laser (ie, scarring) need to be taken into consideration 3-4 monthly anti-VEGF injections Assess presence of fluid on OCT after 3 months and obtain angiogram after 6 months YES
NO fluid + improvement in vision
Mild intraretinal fluid on OCT + stable vision
Continue treating as long as there is an improvement on OCT and vision is stable
Consider monthly monitoring + prn
Consider monthly monitoring and treatment if no improvement in fluid
When there is no longer an improvement
If significant fluid re-appears, consider re-treatment Clinical judgment is required
Perform angiogram and consider the following:
1. Close monitoring (if satisfactory improvement)
2. Intravitreal steroids (especially if other treatments are failing)
3. Vitrectomy and membrane peeling if there is macular traction Clinical judgment is required
To consider • It takes time for neovascularization to regress after photocoagulation (2–3 months). During this time, clinicians could consider an anti-VEGF therapy. • Visual function and visual field should be taken into consideration when evaluating diabetic ocular disease and response to the therapy. • Laser treatment is difficult to administer as it involves grid and requires calculations to apply the proper number of burns, especially when using low-intensity therapy. These many factors to consider in the use of photocoagulation in the treatment of DR and DME in clinical practice result in significant variation in visual outcomes. • It is likely that the future of DR and DME treatment will include a combination of photocoagulation and anti-VEGF therapy. Consensus recommendations 11. PRP remains the gold standard for prevention of proliferation in high-risk DR (Algorithm II). [Level 117,101-103] 12. Current evidence indicates that for the treatment of DME laser is not superior to anti-VEGF therapy. Algorithms IV and V present the 10
BEST PRACTICE STANDARDS IN DR AND DME
The Role of Vitrectomy in the Treatment of DME
The principal indications for vitrectomy include posterior hyaloid traction and diffuse DME that is not responding to conventional therapies with laser or pharmacological approaches, alone or in combination.119-122 Algorithm VII presents the recommendation for the use of vitrectomy in the management of DME. Lewis et al123 suggested in 1992 that vitrectomy can result in improved visual function in eyes with posterior hyaloid traction. It is hypothesized that in these cases vitrectomy relieves traction on the macula from the contracted vitreous and thereby also reduces edema. Two studies conducted in the early 2000s demonstrated that vitrectomy with epiretinal membrane (ERM) peeling reduces edema and improves VA.124,125 Furthermore, the outcome of the procedure did not depend on the presence or absence of posterior vitreous detachment and ERM.124 However, the investigators noted that postoperative reduction in retinal thickness was not completed until 4 months after the procedure. In addition, as vitrectomy might be associated with severe complications, they suggested careful preoperative and postoperative examinations. In a more recent study conducted in 87 patients on behalf of DCRC. net, vitrectomy produced mixed results.118 Although there was 50% reduction in retinal thickening in 68% of patients and 38% of patients had an improvement of ≥10 letters in BCVA, VA decreased by ≤10 letters in 22% of patients. Based on these results, the authors estimated that between 28% and 49% of eyes with DME and vitreomacular traction will have some degree of visual improvement, while 13% to 31% will have a reduction in vision.119 The results of several studies that evaluated the effect of vitrectomy with ILM demonstrated that vitrectomy with peeling reduces retinal thickness but does not significantly improve VA.126-128 A recent retrospective study involving 32 eyes suggested that preoperative hyperreflective foci in the outer retinal layers detected by SDOCT might predict photoreceptor damage and a poorer prognosis after vitrectomy for DME.129 Evaluation of external limiting membrane (ELM) preoperatively predicts vision improvement more accurately than the photoreceptor inner segment/outer segment (IS/OS) junction and central macular thickness in eyes with DME. Thus, assessment of ELM may allow clinicians to evaluate the outcomes of vitrectomy. In summary, the stage of DME appears of particular importance for vitrectomy outcomes. Clinical evidence is not strong but shows benefits in selected cases. To consider • It is difficult to determine whether edema is a cause of exudation or consequence of inflammatory reaction. Consensus recommendations 13. Vitrectomy should be considered in the presence of macular traction (Algorithm VII). [Level 2119-122] 14. Vitrectomy could be considered if edema is not responding to pharmacological therapy, (Algorithm VII). [Level 3/Consensus] Pharmacological Treatment Modalities Anti-VEGF Therapies
The role of ranibizumab in the treatment of DME
Ranibizumab is a humanized antibody fragment directed at all isoforms of VEGF-A, manufactured specifically for intravitreal use.130
Efficacy and safety of ranibizumab for the treatment of DME was evaluated in several randomized, controlled Phase 2 (READ-251 and RESOLVE52) and Phase 3 (RESTORE,53 RISE and RIDE,50 and DRCR. net54,55) clinical trials (Table 4). In all trials, ranibizumab was superior to the control arm (laser, sham, or steroids) in improving visual and anatomic (OCT) outcomes. It is also important to note that ranibizumab was effective in improving vision regardless of glycemic control and hemoglobin A1c levels. One must keep in mind, however, that these trials differ in regard to treatment schedules. Patients enrolled in the RESTORE and DRCR.net trials received a loading dose of 3 monthly injections, followed by monthly monitoring and as needed (pro re nata [prn]) treatment as per study protocol. Patients participating in the RISE and RIDE trials received continuous ranibizumab injections for 3 years.
Table 4. Randomized, Controlled Studies Evaluating Effectiveness of Ranibizumab in DME
Study
Endpoint
Mean change in BCVA 126 READ-2
51
(Phase 2)
RESOLVE52 (Phase 2)
•
Ranibizumab 0.5 mg: +7.2 letters (P=0.01 vs. laser alone)
•
Focal/grid laser: -0.4 letters
•
Ranibizumab 0.5 mg + focal/grid laser: +3.8 letters
6 months
Mean gain in BCVA 101
•
Ranibizumab 0.5 mg: +7.7 letters
•
Focal/grid laser: +5.1 letters
•
Ranibizumab 0.5 mg + focal/grid laser: +6.8 letters
24 months
Change in BCVA from baseline 151
•
Ranibizumab (0.3 and 0.5 mg)*: +10.3 letters (P<0.0001)
•
Sham (laser): -1.4 letters
12 months
Mean change in BCVA
The latest evidence from the RISE, RIDE, and DRCR.net trials also suggests that DME patients treated with ranibizumab have a significantly lower risk of developing PDR than those receiving sham.56,57 Treatment with ranibizumab also appears to prevent progression of existing retinopathy, regress 2 steps of DR stage in one-third of patients and improve visual and anatomical outcomes in these patients.
RESTORE53
The role of bevacizumab in the treatment of DME
(Phase 3)
Evidence for intravitreal bevacizumab (1.25 or 2.5 mg) for the treatment of DME comes from small clinical trials and retrospective case studies.131-135 This carries several significant limitations that need to be taken into consideration when interpreting the data. The Bevacizumab or Laser Therapy (BOLT) study is currently the largest available trial and provides the highest level of evidence for bevacizumab in the treatment of DME.136,137 BOLT was a single center, Twoyear, Phase 2 trial comparing the effects of repeated intravitreal bevacizumab and laser therapy in 80 patients with persistent DME causing moderate visual impairment.136 2-year result demonstrated a mean gain of +8.6 letters in patients treated with bevacizumab compared with -0.5 letters with laser.137 The proportion of patients who gained ≥10 letters was significantly greater for bevacizumab than for laser (49% versus
Study groups and visual outcomes
N
(Phase 3)
345
•
Ranibizumab 0.5 mg: +6.8 letters (P<0.0001 vs. laser alone)
•
Focal/grid laser: +0.9 letters
•
Ranibizumab 0.5 mg + focal/grid laser: +6.4 letters (P=0.0004 vs. laser alone)
12 months
Mean change in VA DRCR.net
•
Ranibizumab 0.5 mg + prompt laser: +9 letters (P<0.001 vs. sham)
•
Ranibizumab 0.5 mg + deferred laser: +9 letters (P<0.001 vs. sham)
•
Triamcinolone 4 mg + prompt laser: +4 letters
•
Sham + prompt laser: +3 letters
54
854
12 months
Mean change in VA DRCR.net55
•
Ranibizumab 0.5 mg + deferred laser: +9.7 letters (P=0.02)
•
Ranibizumab 0.5 mg + prompt laser: +6.8 letters
361
3 years
≥15 letter gain RISE50
377
•
Ranibizumab 0.3 mg: 44.8% (P<0.0001 vs. sham)
•
Ranibizumab 0.5 mg: 39.2% (P<0.001 vs. sham)
•
Sham: 18.1%
3 years
≥15 letter gain RIDE50
382
•
Ranibizumab 0.3 mg: 33.6% (P<0.0001 vs. sham)
•
Ranibizumab 0.5 mg: 45.7% (P<0.0001 vs. sham)
•
Sham: 12.3%
3 years
* Pooled data BCVA = best-corrected visual acuity
BEST PRACTICE STANDARDS IN DR AND DME
11
Algorithm V
Treatment of Clinically Significant Macular Edema without Vitreomacular Traction Without Evidence of Central Macular Thickening
Focal Laser or anti-VEGF
Clinical reassessment +/- OCT at 3 months post treatment
Algorithm VI
Treatment of Clinically Significant Macular Edema with Vitreomacular Traction With Evidence of Vitreomacular Traction
May Consider anti-VEGF
If traction present on OCT consider vitrectomy If persistent or severe traction, consider vitrectomy surgery
7%, P=0.001). Furthermore, no patient treated with bevacizumab lost ≥15 letters while 14% of patients in the laser group sustained a ≥15 letter loss (P= 0.03). A recent small scale prospective randomized trial that included 63 eyes with center-involved DME compared intravitreal bevacizumab (1.5 mg) with ranibizumab (0.5 mg).138 Although at 1 year both agents show similar efficacy in regard to VA and central subfield thickness (CSFT), treatment with ranibizumab led to faster reduction in CSFT and faster recovery of BCVA. The mean number of injections was higher in the bevacizumab group.
The emerging role of aflibercept in the treatment of DME Aflibercept (VEGF Trap-Eye) is a fusion protein that targets VEGF-A, VEGF-B, and placental growth factor (PGF).139,140 In the Phase 2 Da Vinci trial, aflibercept (0.5 mg or 2 mg every 4 weeks and 2 mg every 8 weeks) was superior to laser in improving vision and reducing central retinal thickness (CRT) at weeks 24 and 52.141,142 At week 52, greater percentages of patients treated with aflibercept 12
demonstrated improvement in their Diabetic Retinopathy Severity Score (DRSS) compared with the laser group (31%–64% for aflibercept groups versus 12% for laser).142 In addition, eyes treated with aflibercept were less likely to have worsening of their DRSS compared with laser-treated eyes. This suggests that the biologic activity of aflibercept not only treats DME, but can also reduce the severity of DR, thus changing the natural history of the disease. The 2 Phase 3 trials – VIVID (conducted in the United States) and VISTA (conducted in Europe, Japan, and Australia) – confirmed the superiority of aflibercept to laser.143 In these trials, two doses of aflibercept were tested: 2 mg either every 4 weeks (q4w) or every 8 weeks (q8w). The q8w dose showed similar efficacy to the q4w dose. The mean improvement in BCVA ranged from 10.5 to 12.5 letters. However, the see-saw pattern in CRT, similar to that observed with the same dosing regimen in age-related macular degeneration (AMD),144 suggests that q8w dosing might be suboptimal for some patients. Furthermore, the number of treatments in the Da Vinci trial during the prn phase was similar to that recorded with ranibizumab in the RESTORE53 and DRCR.net studies,54,55 indicating that aflibercept does not carry a dosing advantage. It is also important to keep in mind that, similar to bevacizumab, aflibercept is a full-length antibody and that the Fc portion might increase its systemic exposure. In the Da Vinci, VIVID, and VISTA trials, treatment with aflibercept was generally well tolerated. There was no difference in serious systemic adverse events, including cardiovascular, cerebrovascular and peripheral vascular arterial thromboembolic events as per Antiplatelet Trialists’ Collaboration criteria.145,146 Algorithms III–VI illustrate the recommended use of antiVEGF therapy, ranibizumab in particular, in the management of DME. To consider • Signs of macular edema on OCT should be taken into consideration when deciding whether to treat/retreat. • The fixed monthly schedule used in the RISE and RIDE trials produce the best outcomes. However, this schedule is associated with considerable burden for both DME patients and treating clinicians. • The concomitant use of laser may lower the frequency of anti-VEGF injections, not improving visual outcomes. However, evidence regarding the appropriate timing of laser in relation to anti-VEGF injection
BEST PRACTICE STANDARDS IN DR AND DME
is lacking. In the clinical trials the laser was applied 3 months after initiation of ranibizumab treatment. Recent innovations in laser techniques may further contribute to improved efficacy and safety outcomes while reducing the burden of treatment. • When selecting DME treatment, clinicians should take into consideration approved indications in their respective countries. • Aflibercept data further confirm the effectiveness of targeting the VEGF pathway in treating DME. Long-term data from Phase 3 trials are needed to make any further conclusions. Consensus recommendations 15. The available data have established ranibizumab, with or without laser, as the gold standard for the treatment of DME. The expected average gain in vision based on available evidence is between 8 and 12 letters. [Level 151-55] Bevacizumab data support the evidence that anti-VEGF therapy is effective in treating DME; however, there is less evidence to support its recommendation. The BOLT trial is the largest randomized trial with bevacizumab in DME performed to date. [Level 2136,137] Clinicians should be aware that bevacizumab is not approved for intravitreal administration and assume responsibility for off-label use. However, the risk of not treating is higher than the risk of using the off-label drug. [Level 3/Consensus] 16. DME patients should receive monthly ranibizumab injections for at least 3 to 6 consecutive months (loading dose), until the patient is considered stable. The loading phase should be followed by monthly assessment visits (vision, OCT). [Level 1124,125,127,128] 17. Retreatment criteria should be based on patient individual characteristics and response to therapy. [Level 3/Consensus] 18. Laser could be applied any time after initiation of ranibizumab. [Level 3/ Consensus] Corticosteroids for the Management of DME Due to its anti-inflammatory and, to some extent, antiangiogenic and antipermeability properties, the synthetic steroid
triamcinolone is considered an important tool in the management of DME.103,147 The first commercially available triamcinolone formulation was Kenalog®. Its first use in ophthalmology was in the prevention of proliferative vitreoretinopathy after retinal detachment surgery.148,149 It is also used off-label to manage DME.150,151 However, preservatives in the Kenalog preparation (ie, benzyl alcohol) can cause intraocular inflammation (~8% of treated patients).150,152-154 On the other hand, preservative-free micronized (smaller crystals) triamcinolone (Triesence®, Trivaris®) seems to cause less damage to the neuroretina compared to the regular compound.155,156 Clinical evidence pointed out marked improvement in VA and reduction in retinal thickness after a single dose of triamcinolone.147 Furthermore, Gillies et al157 demonstrated triamcinolone efficacy in treating laserrefractory DME. After 5 years, 42% of cases showed an improvement of 5 letters. Another study confirmed that the use of triamcinolone prior to laser doubles the chance of improving vision by ≥10 letters.158 The incidence of ocular hypertension (~25% of patients experience a temporary increase in intraocular pressure) and cataract (83% of patients over 3 years with a 4-mg dose) may be an issue. It is important to keep in mind that the DRCR.net trial established superiority of laser over triamcinolone.103 However, a subanalysis of this trial showed no difference in vision gain between ranibizumab and triamcinolone in pseudophakic eyes.54 Recently, two steroid implants have been evaluated in the treatment of DME.159,160 Ozurdex® is a slow-delivery dexamethasone biodegradable implant that is injected into the vitreous. The superiority of Ozurdex to sham plus laser was observed during the first 9 months after the procedure, but there was no significant difference between treatment arms at 1 year.159 Furthermore, five procedures were required to control edema over 3 years. In a Phase 2 trial that included 55 vitrectomized eyes, reduction in central macular thickness and improvement in vision lasted 6 months.160 This suggests that Ozurdex might provide a window of opportunity in these patients during which the efficacy of other therapeutic modalities can be ameliorated. Iluvien®, a 25-mg implant that contains 190 µg of fluocinolone, has been recently approved in Europe further to the results of the FAME trial.161 Iluvien, on a 12-month retreatment schedule and the ability to use laser 6 weeks after implantation and every 3 months afterwards, was superior to sham injections at 3 years. To consider: • As steroids have only minor antiangiogenic effects, they treat only a part of DME pathology. • The benefits associated with steroids are tempered by concerns about issues such as ocular hypertension and the development of cataracts. • Frequent follow-up required after Ozurdex implantation presents a significant burden on both clinician and patient. Furthermore, the effects of steroids start wearing off after 2 months. Thus, this therapeutic approach is associated with “lots of work and little gain”. Consensus recommendations 19. As initial improvement in vision and reduction in edema obtained with steroids is unsustained, steroids should not be used as monotherapy, but rather in combination with other therapeutic modalities. [Level 3/Consensus]
Algorithm VII - Vitrectomy Vitrectomy
Hemorrhage Non-clearing Vitreous Hemorrhage Clearing but Frequently Recurring Vitreous Hemorrhage
Consider VEGF inhibitors preoperatively to reduce hemorrhage (if no tractional elements; avoid if there is significant fibrosis or contraction)
Tractional Detachments Tractional Macular Detachment Tractional Rhegmatogenous Detachment
Clinical judgment is required when considering preoperative anti-VEGF Consider VEGF inhibitors postoperatively to reduce hemorrhage and complications associated with vitrectomy
20. Fast reduction in edema achieved with steroids provides a window of opportunity for the use of other therapeutic approaches such as laser or anti-VEGF therapy. [Level 2160] 21. Steroids might be considered for pseudophakic patients (algorithm IV). [Level 254] Distinguishing Between Responders and Nonresponders To consider: • Duration of edema can be used as a predictor of response to therapy: the longer the duration of edema, the poorer the outcome. • For the definition of a nonresponder, the DCRC.net protocol may be considered. • For monitoring of patient response to therapy, the use of the ETDRS chart is preferred over the Snellen chart. Consensus recommendation 22. While a patient with clear improvement in vision and anatomy is considered a responder, a patient with no change in VA after 3–6 monthly anti-VEGF injections and no change in OCT (improvement of at least 30–50 µm after a second injection is expected) should be deemed a nonresponder. For this patient a change in therapy should be considered. [Level 3/Consensus]. Safety of Pharmacological Therapies in the Management of DME Differences in the molecular structure of 3 anti-VEGF agents effective in the treatment of DME are reflected in their pharmacological properties which could potentially account for the differences in their safety profiles.162-166 Ranibizumab, an antibody fragment of approximately 48 kDa, was designed specifically for intravitreal use.130,167 Bevacizumab and aflibercept, on the other hand, are full-length antibodies initially developed for intravenous administration in oncology patients.168,169 While systemic elimination of ranibizumab after intravitreal use is approximately 2 hours,167 systemic elimination of aflibercept and bevacizumab is significantly longer: 4 to 5 days for aflibercept139,170 and about 20 days BEST PRACTICE STANDARDS IN DR AND DME
13
for bevacizumab.169 Transport from the eye across the BRB into the systemic circulation is attributed to the Fc fragment of the molecule and its receptors expressed on multiple ocular tissues.171,172 Affinity for VEGF also differs between intravitreal anti-VEGF therapies.173 Ranibizumab has a high affinity for VEGF-A and aflibercept for VEGF-A, VEGF-B, and PGF.174,175 It is still unclear what role aflibercept’s broad spectrum of affinity may play outside the eye, especially since the latest data indicate a neuroprotective effect of VEGF-B.176 As VEGF plays a significant role in angiogenesis, vascular repair, and homeostasis, its systemic suppression can elicit potential deleterious effects on multiple organ systems.177,178 For example, it has been shown that suppression of anti-VEGF in cancer patients carries numerous adverse consequences such as compromised wound healing, hypertension, arterial thrombosis, cardiac dysfunction, proteinuria, and renal adverse effects.178 This potential to compromise systemic safety is of particular importance when selecting therapy for diabetic patients who are already at high risk of cardiovascular and renal complications. It must be noted that clinical trials that assess anti-VEGF therapies in the treatment of ocular conditions have not been powered to compare their systemic safety. As ranibizumab has been developed and approved for intravitreal use and treatment of ocular diseases, its safety profile has been proven and established based on several large clinical trials.179,180 These trials subsequently led to the regulatory approval of the drug in various ocular conditions, including AMD and DME. In large clinical trials ocular events were similar between sham and ranibizumab. On the other hand, off-label use and reconstitution required to prepare bevacizumab for intraocular use have been linked to cases of severe bacterial endophthalmitis that have resulted in poor visual outcomes.181,182 Thus, clinicians should keep in mind that bevacizumab is not approved for intraocular use and, as such, needs to be reconstituted by a compounding pharmacy. High-molecularweight aggregates were also found in
14
repackaged bevacizumab.183,184 This may lead to obstruction of aqueous overflow and subsequent elevation in intraocular pressure and glaucoma.185,186 Rates of cardiovascular events observed in ranibizumab clinical trials were low and in line with the rates observed in the general population.179 On the other hand, safety signals from two large trials in AMD patients suggest a higher incidence of serious adverse events, especially gastrointestinal complications with bevacizumab compared to ranibizumab.162,163 This parallels the black box warning for intravenous bevacizumab that includes compromised wound healing and gastrointestinal perforation.169 A similar warning is included on the Zaltrap® (intravenous formulation of aflibercept) label.186 In summary, although the safety signals from clinical trials regarding intravitreal administration of antiangiogenics might be small, treating clinicians should take into consideration that patients in clinical practice differ from those included in clinical trials. Comorbidities might further contribute to unwanted adverse events. In regard to intraocular steroids, it is well established that their use leads to increases in intraocular pressure, glaucoma, and potentially cataract.157,158,187-189 Laser is associated with scarring complications.97,190-192 To consider: • Diabetic patients might be more difficult to treat than patients with AMD and retinal vein occlusion due to the systemic nature of the disease and associated comorbidities. Consensus recommendations: 23. Data from large clinical trials established a favorable safety profile for ranibizumab. Furthermore, the safety profile of ranibizumab in DME is consistent with that observed in AMD patients. [Level 1179,180] However, as safety data for other antiangiogenics (bevacizumab and aflibercept) are missing, pharmacovigilance is required. In addition, clinicians should be aware that bevacizumab is not indicated for intravitreal administration. [Level 3/Consensus] 24. As intravitreal steroids can lead to an increase in intraocular pressure,
BEST PRACTICE STANDARDS IN DR AND DME
glaucoma, and cataract, caution and frequent patient follow-up is required [Level 1157,158,187-189]. 25. Clinicians should take into consideration that treatment with laser might lead to scars and related complications. [Level 197,190-192] 26. General health status of diabetic patients needs to be taken into consideration when selecting therapy for DME. [Level 3/Consensus] 27. Clinicians should ensure that the highest aseptic standards are applied during the administration procedure. [Level 3/Consensus] Cataract and DME Diabetic patients are 2 to 4 times more likely to develop cataract when compared to nondiabetic patients.193 The risk is higher in patients with proliferative DR, those who are older than 40 years, and in insulindependent patients.194 The relationship between cataract surgery and the natural history of DR is unclear. It is also uncertain to what extent treatment of DR and DME prior to cataract surgery impacts its outcome. Three main situations to consider include: • Patients in need of cataract surgery without the need for retinopathy treatment • It has been demonstrated that patients with pre-existing retinopathy are at increased risk of progression of retinopathy, development of macular edema, and vision loss compared to those without pre-existing retinopathy195 • Patients in need of both cataract surgery and vitrectomy • Although several studies have proven that visual prognosis is similar when both procedures are done simultaneously, sequential procedures are preferred from the patient’s standpoint196,197 •
Patients with clear lens in need of vitrectomy without cataract surgery In all cases, preoperative evaluation is essential and should include evaluation of VA, fundus evaluation, OCT, and ultrasound. Although the causes of macular edema post cataract surgery are not completely understood, it is suspected that inflammatory cytokines, vasoactive mediators, and hyaloid membrane
traction might play a role.198 As VEGF contributes to a number of phenotypic changes seen in macular edema,199 recent studies showed that the use of intravitreal antiangiogenics combined with phacoemulsification may prevent the development of postoperative DME following cataract surgery.200-206 To consider: • It is unclear whether post-cataract surgery edema in diabetic patients is “true” DME or just a post-surgical edema that can be treated with nonsteroidal anti-inflammatory eye drops. • OCT might be helpful in determining whether the edema is in the outer or inner nuclear layer. • As DME usually affects the outer layer, this might be used to guide therapeutic options. • Preoperative anti-VEGF might prevent development of post-surgical edema, but the evidence is weak. • Large retinal cysts should be treated prior to cataract surgery as they might break during the procedure and damage the retina.
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Consensus recommendations 28. The first step in the treatment of post-cataract surgery edema in diabetic patients is the “watch and wait” approach for 1 to 2 months or nonsteroidal anti-inflammatory eye drops. In case of persistent edema, intravitreal steroids or antiangiogenics can be considered. [Level 3/Consensus]
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29. Treatment of existing DME prior to cataract surgery needs to be well documented. [Level 3/Consensus] 30. Patients with DME need to have the edema under control (treated, stable, and responding to treatment) prior to cataract surgery. [Level3/Consensus] 31. If after the cataract surgery edema develops in the fellow eye, it should be examined and treated independently. [Level3/ Consensus]
6.
7.
Emerging Therapies As VEGF plays a major role in pathogenesis of DR and DME, research that targets the VEGF signaling pathway (ie, degradation of VEGF messenger ribonucleic acid [RNA] using small interfering RNAs, blockade of VEGF receptors, etc.) continues.207 In addition, other cytokines implicated in the pathogenesis of the disease (ie, tumor necrosis factor),208 protein kinase C,209 and mammalian target of rapamycin210 are being investigated. Other therapeutic modalities in the early stages of clinical development include genetic therapy,211,212 antisense technology that uses an antisense strand of oligonucleotides that bind to and inhibit specific messenger RNA,213 integrin peptide therapy,214 and designed ankyrin repeat proteins.215 In addition, other readily available options should not be neglected in difficult cases, like surgical approaches,216,217 new laser modalities218 and steroidal implants.160 To consider: •
Antiangiogenics have set the bar very high, making it difficult for novel therapies to meet their efficacy, safety, convenience of administration, and cost.
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Definición de estándares de buenas prácticas para el diagnóstico y tratamiento de la retinopatía diabética y el edema macular diabético en América Latina Schlottmann P.1, Acosta C.2, Alezzandrini A.A.3, Bafalluy J.4, Biccas L.5, Hidalgo Cano6, Damico F.M.7, Dib G.8, Fromow-Guerra J.6, Jorge R.9, Lavinsky D.10, Morales-Canton V.11, Roca J.A.12, Farah *M.E.13
Organización Médica de Investigación, Buenos Aires, Argentina. 2Universidad CES, Medellín, Colombia,3Universidad de Buenos Aires, Argentina, 4Universidad Nacional de Rosario, Rosario, Argentina, 5Clínica Ocular Oftalmologia, Vitória, Brasil, 6Universidad Nacional Autónoma de México, Ciudad de México, México, 7 Universidade de São Paulo, Brasil, 8Universidad del Zulia, Maracaibo, Venezuela, 9Universidade de São Paulo, Ribeirão Preto, Brasil, 10Universidade Federal do Rio Grande do Sul, 11Asociación para Evitar la Ceguera en México, Ciudad de México, México, 12Universidad Peruana Cayetano Heredia, 13 Universidade Federal de São Paulo, Brasil. 1
*Dirección para correspondencia: M.E. Farah, mefarah@uol.com.br
Resumen Objetivo: Ofrecer recomendaciones y orientación basadas en la evidencia para el tratamiento de la retinopatía diabética (RD) y del edema macular diabético (EMD) según la evidencia clínica publicada recientemente y la experiencia clínica. Métodos: Se realizó una búsqueda bibliográfica en las bases de datos PubMed y Cochrane utilizando los términos “edema macular diabético” o “retinopatía diabética” para identificar los estudios publicados de enero de 2008 a noviembre de 2013. Después de esto se realizó una búsqueda manual de referencias citadas en artículos selectos publicados en revistas revisadas por expertos, y se realizó una búsqueda manual de referencias citadas en artículos selectos publicados en revistas científicas revisadas por expertos. Los miembros del panel de expertos en EMD de América Latina revisaron las referencias identificadas en estas búsquedas de bibliografía y las presentaron ante el grupo en pleno durante la reunión de consenso, de dos días de duración. Durante esta reunión, los expertos formularon recomendaciones teniendo en cuenta los beneficios, riesgos y efectos adversos de las intervenciones para la salud. Se asignó a las referencias utilizadas como respaldo de las recomendaciones un nivel de evidencia basado en el sistema de clasificación de evidencias SORT (Strength of Recommendation Taxonomy) referente a la fortaleza de la recomendación. Resultados: Se formularon 31 recomendaciones consensuadas. Entre ellas se incluyeron la recomendación del control glucémico precoz en pacientes diabéticos a fin de reducir el riesgo de avance de la
20
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
enfermedad ocular. El panel de expertos recomendó también la recolección de datos epidemiológicos para definir mejor la prevalencia de la RD y el EMD en América Latina, y definir algoritmos para el manejo y tratamiento en varios estadios de la enfermedad. Se hace un mayor énfasis en la necesidad de evaluación precoz y del desarrollo de infraestructura para garantizar a quienes necesitan un seguimiento y tratamiento adecuados. Tanto la angiografía con fluoresceína (AF) y la tomografía de coherencia óptica (TCO) son necesarias para la evaluación adecuada de la evolución de la enfermedad y la respuesta a la terapia. Sobre la base de evidencias de alto nivel, recomendamos el ranibizumab como la regla de oro para el tratamiento del EMD y la fotocoagulación panretiniana (FPR) como la regla de oro para la RD. Debe tenerse en cuenta una vitrectomía ante la presencia de una tracción macular o si el edema no responde a la farmacoterapia. Como los esteroides intravítreos generan una reducción del edema, se pueden usar para mejorar los efectos de otros tratamientos y también en ojos pseudofáquicos. Finalmente, al seleccionar un tratamiento para la RD o el EMD, es particularmente importante tener en cuenta el estado de salud general del paciente. Conclusión: Si bien estas pautas no pretenden ser un reemplazo del criterio clínico, deben ayudar a optimizar el tratamiento del EMD en América Latina y garantizar que los pacientes reciban la mejor atención disponible en tiempo y forma. Introducción El objetivo del presente documento es ofrecer pautas a los oftalmólogos y
especialistas en retina latinoamericanos acerca del diagnóstico y el tratamiento de la retinopatía diabética (RD) y el edema macular diabético (EMD). Las recomendaciones descritas se desarrollaron sistemáticamente sobre la base de un profundo análisis de la bibliografía médica y la experiencia clínica. No obstante, estas pautas no pretenden sustituir el criterio clínico; por el contrario, su intención es informar acerca de los patrones de práctica. Además, este documento no se puede utilizar como recurso legal, ya que no ofrece pautas personalizadas para todos los pacientes en todas las situaciones. De hecho, al tener en cuenta los abordajes terapéuticos para pacientes diabéticos con compromiso ocular, los oftalmólogos deben tener en cuenta las necesidades, preferencias, valores y contexto económico y personal de cada paciente separadamente y trabajar dentro de las realidades de su entorno de atención médica. Se entiende que hay desequilibrios en los recursos humanos, financieros y de atención médica en países y regiones de América Latina y que dichos factores podrían afectar las preferencias, las opciones y las decisiones de los médicos y de los pacientes. Métodos Se realizó una búsqueda bibliográfica en idioma inglés en las bases de datos PubMed y Cochran utilizando los términos “diabetic macular edema” (edema macular diabético) o “diabetic retinopathy” (retinopatía diabética) para identificar los estudios publicados de enero de 2008 a noviembre de 2013. Después de esto se realizó una búsqueda manual de referencias citadas en artículos selectos
publicados en revistas científicas revisadas por expertos. Las fuentes preferidas fueron metaanálisis, revisiones sistemáticas y ensayos clínicos aleatorizados con al menos 1 año de seguimiento, publicados dentro de los últimos cinco años. Las referencias identificadas por los investigadores de bibliografía fueron revisadas por los miembros del panel de expertos en EMD de América Latina; cada uno de los miembros revisó las referencias correspondientes a su tema respectivo a fin de asegurarse de que fueran relevantes y de calidad metodológica aceptable. Los miembros del panel de expertos presentaron además evidencia clave ante todo el grupo durante una reunión de consenso, de dos días de duración, que tuvo lugar el 13 y 14 de noviembre en Miami, Florida. Durante esta reunión, los expertos revisaron la evidencia y formularon recomendaciones teniendo en cuenta los beneficios, riesgos y efectos adversos de las intervenciones para la salud. Se asignó a las referencias utilizadas como respaldo de las recomendaciones un nivel de evidencia basado en el sistema de
Anexo 1. Evaluación de la calidad de la evidencia - Clasificación de la fortaleza de la recomendación (SORT)
Calidad del estudio Nivel 1: Buena calidad evidencia orientada al paciente
Diagnóstico
• • •
Nivel 2: Calidad limitada evidencia orientada al paciente
• •
•
Nivel 3: otra evidencia
Tratamiento/ prevención/evaluación
Norma de decisión clínica validada • RS/metaanálisis de • estudios de alta calidad • Estudio de cohortes de diagnóstico de alta calidad* •
Norma de decisión clínica no validada RS/metaanálisis de estudios de calidad inferior o estudios con hallazgos inconsistentes Estudio de cohortes de diagnóstico de inferior calidad o estudio de control de casos para diagnóstico
• • •
Pronóstico
• RS/metaanálisis o ECA con hallazgos consistentes ECA individual de alta calidad† • Estudio “todos o ninguno”‡ RS/metaanálisis de ensayos clínicos de calidad inferior o de estudios con hallazgos inconsistentes Ensayo clínico de calidad inferior Estudio de cohortes Estudio de control de casos
•
•
• •
RS/metaanálisis de estudios de cohortes de buena calidad Estudio prospectivo de cohortes con buen seguimiento RS/metaanálisis de estudios de cohortes de calidad inferior o estudios con resultados inconsistentes Estudio de cohortes retrospectivo o estudio de cohortes prospectivo con mal seguimiento Estudio de control de casos Serie de casos
Pautas consensuadas, extrapolaciones de investigaciones en laboratorio, práctica habitual, opinión, evidencia orientada a la enfermedad (solo resultados intermedios o fisiológicos) o series de casos para estudios de diagnóstico, tratamiento, prevención o evaluación.
*Estudio de cohortes de diagnóstico de alta calidad: diseño de cohortes, tamaño adecuado, espectro adecuado de pacientes, ocultación y un estándar de referencia bien definido. † ECA de alta calidad: asignación oculta, ciega si es posible, análisis de la intención de tratar, poder estadístico adecuado, seguimiento adecuado (más del 80 %). ‡ En un estudio de “todos o ninguno”, el tratamiento provoca un cambio drástico en los resultados, como p. ej., antibióticos para meningitis o cirugía para apendicitis, lo que impide realizar estudios en ensayos controlados.
RS = revisión sistemática; ECA ensayo controlado aleatorizado Usado y adaptado con autorización de: Ebell MH, Siwek J, Weiss BD, Woolf SH, Susman J, Ewigman B, Bowman M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):548-556.
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Algoritmo I Evaluacióna para retinopatía diabética Diabetes tipo 1 diagnosticada después de la pubertad
Diabetes tipo 1 diagnosticada antes de la pubertad
Diabetes tipo 2
La evaluación debe iniciarse 5 años después del diagnóstico de diabetes
La evaluación debe iniciarse en la pubertad (Salvo que haya otros factores que se deben tener en cuenta y que sugieran la necesidad de un examen precoz)
La evaluación debe iniciarse en el momento del diagnóstico
Presencia de retinopatía no proliferativa Leve
Moderada
Grave
Examen anual
Seguimiento cada 6 meses
Seguimiento cada 3 meses
Presencia de retinopatía proliferativa SI Leve examen anual
NO Moderada o grave examen cada 3-6 meses
Examen anual en todos los tipos de diabetes
Los algoritmos relacionados a continuación se usan con permiso de los algoritmos de tratamiento del EMD canadienses (Hooper P, et al. Ophthalmologica. 2014;231(1):215). Los algoritmos se modifican más con permiso para reflejar la práctica actual y los requisitos de los países latinoamericanos. La valoración de evaluación debe incluir: 1. medición de la agudeza visual, 2. presión intraocular, 3. TCO para evaluar la presencia de edema macular, 4. biomicroscopía para evaluar la presencia de neovascularización del iris y el ángulo, 5. fotos de fondo de ojo para documentar, clasificar los estadios y comparar la evolución de la enfermedad.
a
clasificación de evidencias SORT (Strength of Recommendation Taxonomy) referente a la fortaleza de la recomendación (Anexo 1). En ausencia de evidencia directa, se redactaron recomendaciones que reflejaran el consenso unánime del panel de expertos.
se caracteriza por síntomas de poliuria (micción frecuente), polidipsia (aumento de la sed) y polifagia (aumento del hambre). La DM no tratada puede llevar a varias complicaciones macro y microvasculares, incluyendo la RD y el EMD.2
Las pautas resaltan los puntos clave de los datos de dos maneras. 1. Los puntos “a tener en cuenta” son extrapolaciones clave de los datos y de la práctica clínica diaria considerados importantes pero para los cuales no hay evidencia publicada que sea lo suficientemente sólida. Por consiguiente, no se les asignó una ponderación basada en la evidencia. 2. Las “recomendaciones por consenso” son afirmaciones basadas en la evidencia acerca del manejo de los pacientes y cuentan con el respaldo de la mencionada bibliografía.
El emblemático ensayo sobre control y complicaciones de la diabetes DCCT3 (Diabetes Control and Complications Trial) y su continuación, el estudio de epidemiología de las intervenciones y complicaciones de la diabetes EDIC4 (Epidemiology of Diabetes Interventions and Complications), establecieron que el control glucémico intensivo reduce las complicaciones macro y micro vasculares de la enfermedad en pacientes con DM tipo 1, incluyendo la reducción del riesgo de presentar retinopatías progresivas. Además, en ambos ensayos, los beneficios del tratamiento intensivo se sostuvieron durante un período de tiempo prolongado.5-8
Realidad actual de la diabetes mellitus La diabetes mellitus (DM) incluye a un grupo de enfermedades metabólicas en las que el páncreas no produce suficiente insulina o las células no responden a la insulina que se produce.1 La enfermedad 22
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
No obstante, se debe tener en cuenta que, además de la insulina, la regulación de la glucosa implica otras hormonas y varios sistemas de órganos.9 Además, la insulina
de reposición no imita en forma idéntica las acciones de la insulina segregada por el páncreas. Esto podría ser una explicación posible de algunos de los eventos adversos que se observan en el tratamiento intensivo con insulina, como p. ej., el aumento al triple de la hipoglucemia grave, el aumento al triple de las convulsiones y el coma y el mayor aumento de peso.10 En el estudio prospectivo de diabetes del Reino Unido (United Kingdom Prospective Diabetes Study) se evaluó el rol del control glucémico intensivo en más de 5000 pacientes con DM tipo 2.11 En resumen, el ensayo demostró que el control intensivo de la glucemia y de la presión arterial reduce el riesgo de sufrir complicaciones de la diabetes. Los mayores efectos del estricto control de la glucosa se observaron en la reducción de las complicaciones microvasculares. No hubo grandes diferencias entre las distintas farmacoterapias. Finalmente, en el ensayo de acción para el control del riesgo cardiovascular en diabetes ACCORD (Action to Control Cardiovascular Risk in Diabetes) se evaluó el impacto del control intensivo de la glucemia, de los lípidos y de la presión arterial en resultados relacionados con ECV en más de 10.000 pacientes con diabetes tipo 2 y factores de riesgo establecidos (es decir, evento CV previo, tabaquismo, etc.).12,13 Si bien el control intensivo de la glucemia y de la dislipidemia redujo el índice de evolución de la RD, aumentó el riesgo de muerte en pacientes con alto riesgo de ECV.13,14 A tener en cuenta •
Los ensayos no incluyeron poblaciones de América Latina, por consiguiente, es preciso extrapolar los datos.
•
El tratamiento glucémico intensivo puede estar asociado con un breve período de empeoramiento de la enfermedad ocular en algunos pacientes, principalmente durante los dos primeros años. A fin de controlar rápidamente la evolución de la RD y sus complicaciones que amenazan la visión, secundarias a esta evolución natural inexplicable de la enfermedad, los oftalmólogos y especialistas en retina deben asegurarse de realizar
seguimientos más frecuentes y tratamientos potencialmente más intensivos durante este período inicial. Recomendaciones por consenso 1.
El control glucémico precoz e intensivo en pacientes diabéticos es necesario, ya que reduce el riesgo de evolución de la RD y el EMD en pacientes que no corren alto riesgo de padecer eventos de ECV. [Nivel 15,7,14]
2.
Los oftalmólogos y especialistas en retina deben asegurarse de que sus pacientes diabéticos también sean tratados y sometidos a un seguimiento por especialistas en diabetes, a fin de garantizar óptimos resultados terapéuticos. [Nivel 3/Consenso]
Epidemiología del EMD y carga de la enfermedad Según datos publicados en 2013 por la Federación Internacional de Diabetes, en el mundo entero hay alrededor de 382 millones de personas que sufren de DM.15 Además, se proyecta que esta cifra aumente a 592 millones para el año 2035. La RD y el EMD son complicaciones de la DM relacionadas con problemas microvasculares de los ojos de muy alta prevalencia y debilitantes.16 Si bien la RD está presente en el 35 % de los pacientes diabéticos, alrededor del 8 % desarrollan la forma proliferativa de la enfermedad.16 El EMD, definido como el engrosamiento de la retina dentro del diámetro de dos discos de la fóvea central, puede ocurrir en cualquier etapa de la enfermedad.17 Su gravedad varía de leve y asintomática a pérdida de visión profunda.18 Se estima que entre el 13 % y el 25 % de los pacientes con DM desarrollan EMD en el transcurso de 10 años19 y el mayor riesgo lo corren los pacientes con DM tipo 2 insulinodependientes.20 La prevalencia del EMD también varía según la etapa de la RD, desde un 3 % en pacientes con enfermedad no proliferativa leve a un 71 % en pacientes con una forma más proliferativa.18 El EMD y el EMD de relevancia clínica (EMDRC) parecen ser más prevalentes en poblaciones hispanas y de raza negra en comparación con las personas chinas o caucásicas.21-23 La prevalencia del EMDRC en la población con DM tipo 2 de América del Sur varía entre 3,4 % y ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
23
5,5 %.24 Entre los factores que contribuyen se incluyen cambios en los hábitos de alimentación y un estilo de vida cada vez más sedentario.25 Según el estudio ocular llevado a cabo en latinos Los Angeles Latino Eye Study, 37,4 % de los diabéticos de América Latina tienen RD y 10,7 % tienen EMD.26 Tanto la RD como el EMD tienen consecuencias negativas sobre la calidad de vida e implican una carga económica significativa para el paciente, sus familiares, la sociedad y el sistema de salud.27,28 Respecto a la historia natural, la enfermedad ocular evoluciona desde el engrosamiento de retina a una enfermedad que afecta el centro para finalmente llegar al deterioro de la agudeza visual (AV). Si no se trata, se perderán 15 letras del Estudio de tratamiento precoz de la retinopatía diabética ((Early Treatment Diabetic Retinopathy Study - ETDRS)) en el transcurso de tres años y el pronóstico general es malo.17 Esto destaca la necesidad de la evaluación, la detección y el tratamiento precoces.29,30 El algoritmo 1 presenta las recomendaciones relacionadas con la evaluación para casos de RD no proliferativa y proliferativa. Como la teleoftalmología se restringe al diagnóstico de enfermedades oculares, solo resulta beneficiosa en áreas donde posteriormente se pueda ofrecer tratamiento.31 A fin de mejorar el tratamiento de la enfermedad ocular diabética y reducir su impacto en los pacientes, en la economía y en los sistemas de salud, se necesitan programas de conciencia pública y estudios epidemiológicos.16,32 Se necesitan más investigaciones en el futuro para entender mejor el rol potencial de los factores de riesgo y la predisposición genética para dar forma a programas de salud pública. Algoritmo II Tratamiento de la retinopatía proliferativa En ciertas instanciasb, es de beneficio tratar a los pacientes antes de que desarrollen criterios de alto riesgo Estudio de retinopatía diabética Características de alto riesgo La presencia de cualquiera de los siguientes casos: • Neovascularización • NVD • Gravedad de la neovascularización o NVD > tamaño de ¼ área de disco o NVE > tamaño de ½ área de disco •Hemorragia prerretiniana o vítrea
b Pacientes que viven lejos de la clínica, evidencia de enfermedad de rápida evolución, cumplimiento cuestionable, pacientes con diabetes tipo 2 o pacientes mayores.
NO
FPRc
Realizar seguimiento post-FPR luego de 3 meses Los vasos están creciendo o parecen activos
Presencia de hemorragia (visualmente relevante o que no se soluciona)
Aumento de FPR
Anti-VEGF
FPR progresiva luego de FPR máxima
NO
Hemorragia solucionada
Vitrectomía
SI
Aumento de FPR
NVD= Neovascularización del Disco Óptico; NVE= Neovascularización en otro sitio; VEGF= Factor de Crecimiento Endotelial Vascular; ETDRS= Estudio Tratamiento Temprano de la Retinopatía Diabética; RDP= Retinopatía Diabética Proliferativa.
24
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
•
La falta de conciencia sobre la DM y sus consecuencias representa un problema importante en América Latina. Alrededor de la mitad de la población de diabéticos en América Latina no saben que padecen la enfermedad e ingresan en el sistema de salud cuando notan cambios en su visión.
•
Tanto factores genéticos como de estilo de vida contribuyen con la prevalencia en aumento de la DM, la RD y el EMD en América Latina.
•
Los estudios epidemiológicos actuales carecen de definiciones adecuadas de origen étnico. La definición y clasificación de los pacientes según su origen étnico son necesarias para evaluar la predisposición genética al desarrollo de RD y EMD.
•
La escasez de especialistas en retina es un problema considerable en todos los países de América Latina.
Recomendaciones por consenso 3. Todos los países o regiones deben hacer el intento de reunir datos epidemiológicos para evaluar la prevalencia de la DM, la RD y el EMD. [Nivel 3/Consenso] Se deben registrar los distintos métodos de recolección de datos y tenerse en cuenta cuando se interpreten los resultados de los estudios epidemiológicos. [Nivel 3/Consenso] 4. La DM sigue siendo una afección mal definida desde la perspectiva del oftalmólogo. Por consiguiente, es preciso establecer algoritmos para el seguimiento en las varias etapas de la enfermedad. [Nivel 3/Consenso]
Evidencia de edema macular central
Mantenerse alejado de cualquier área de tracción durante la FPR La FPR puede SI estar asociada con riesgo de fibrosis. Es preciso tener precaución. c As per ETDRS criteria FPRc+ Anti-VEGF
A tener en cuenta
5. A fin de tener éxito y lograr una mejora de los resultados de salud, los programas de conciencia pública y de evaluación deben contar con el apoyo de una infraestructura adecuada que garantice el seguimiento y el tratamiento de quienes lo necesiten. [Nivel 3/Consenso] Fisiopatología del EMD El mecanismo exacto mediante el cual la hiperglucemia crónica provoca el desarrollo de RD y EMD no está completamente
comprendido y es muy probable que esté compuesto por varios factores. El camino advanced glycation end-products común comienza con la afección de la barrera hematorretiniana (BHR) interna, lo que da lugar a vasopermeabilidad y movimiento de agua.33,34 La ruptura de la BHR interna es un proceso complejo que implica cambios en la unión estrecha, pérdida de pericitos, pérdida de células endoteliales, leucostasis de los vasos retinianos, sobrerregulación del transporte vesicular y tracción vitreorretiniana. Se notan cambios estructurales y funcionales en las neuronas y el tejido glial en las fases precoces de la enfermedad, mucho antes de que se observen cambios en los vasos.33 La hiperglucemia sostenida afecta varios factores vasoactivos, incluidos el factor de crecimiento endotelial vascular (vascular endothelial growth factor – VEGF), proteína quinasa C (PKC), heparina, angiotensina II y el factor derivado del epitelio pigmentario (pigment epithelium derived factor – FDEP).35-38 Esto conduce a un aumento de la permeabilidad y pérdidas de la BHR.39 El VEGF, la citocina más estudiada de las involucradas en la patogénesis del EMD, es producida por muchas células retinianas.40-46 La hipoxia relacionada con la vasoconstricción y la pérdida de capilares lleva a una sobrerregulación de la expresión del VEGF y a un aumento de la permeabilidad vascular.47,48 Se ha sugerido que algunas formas de PKC también representan un papel importante en la vasopermeabilidad inducida por el VEGF.36 Por ende, no nos sorprende que los inhibidores de la PKC hayan demostrado reducir significativamente las pérdidas de fluoresceína inducidas por el VEGF.36 La evidencia clínica y anatómica indica además que las anomalías en la interfaz vitreorretiniana podrían representar un papel importante en la patogénesis del EMD.49 Por ejemplo, la adhesión de humor vítreo en la mácula está relacionada con un aumento del edema macular. La acumulación de productos finales de glicación avanzada (advanced glycation end-products - AGE) en la corteza vítrea conduce a una mayor adhesión del humor vítreo posterior a la membrana limitante interna (MLI). A tener en cuenta •
Las interacciones y la función de varias citocinas en la patogénesis de
Tabla 1. Terminología de TCO estandarizada por el DRCR.net
Término
Definición
Grosor de la retina
El valor en micrones de la distancia entre las capas de TCO que se asumen que son el epitelio pigmentario de la retina y la membrana limitante interna
Engrosamiento de la retina
El valor calculado equivalente al grosor menos la media de la población para la variable que se tiene en cuenta
Punto central
La intersección de los seis escaneados radiales
Grosor del punto central
El promedio de valores de grosor para los seis escaneados radiales en su punto de intersección
Subcampo central
El área circular de 1 mm de diámetro centrada alrededor del punto central
Grosor promedio del subcampo central
El valor promedio de los 128 valores de grosor obtenidos en el subcampo central
TCO = tomografía de coherencia óptica; DCRC.net = Red de investigación clínica sobre retinopatía diabética Browning DJ et al. Ophthalmology 2008;115(8):1366-1371.
la RD y del EMD aún están por comprenderse en su totalidad. El hecho de que en el 10 % de los pacientes de los ensayos RIDE y RISE50 la enfermedad progresó a 24 meses, pese a la eliminación completa del VEGF, indica el involucramiento de otras rutas. •
Las diferencias en la patogénesis de la enfermedad pueden afectar a las decisiones terapéuticas.
Recomendación por consenso 6.
Si bien son muchos los factores involucrados en la patogénesis de la RD y el EMD, el rol del VEGF en la patogénesis del EMD es el más comprendido. Como tal, la señalización relacionada con el VEGF es el único camino de tratamiento aprobado y recomendado en la actualidad. [Nivel 150-57]
Modalidades de imaginología en el tratamiento del EMD: aplicación de los últimos avances en la práctica médica diaria Rol de la angiografía normal y panorámica en el diagnóstico de EMD La angiografía con fluoresceína (AF) ha representado un rol fundamental en el tratamiento del EMD durante más de medio siglo.58,59 Como los patrones de hiperfluorescencia e hipofluorescencia ofrecen una perspectiva de la fisiopatología de la enfermedad, son útiles para guiar las decisiones terapéuticas.59 Por consiguiente, pese a los avances recientes en otras técnicas de imaginología, incluida la tomografía de coherencia óptica (TCO), la AF sigue ocupando un puesto clave en la evaluación de los resultados terapéuticos.60 Una de las limitaciones de la técnica tradicional de AF es su incapacidad de captar una imagen única de todo el fondo de ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
25
Tabla 2. Escala de gravedad de la retinopatía diabética (RD)
Nivel de gravedad propuesto de la enfermedad
Hallazgos observables en oftalmoscopía con dilatación
Sin retinopatía aparente
Sin anomalías
RD no proliferativa leve
Solo microaneurismas
RD no proliferativa moderada RD no proliferativa grave
Más de simples microaneurismas, pero menos que una retinopatía diabética no proliferativa grave Cualquiera de los siguientes: • 20 hemorragias intrarretinianas en cada uno de los cuatro cuadrantes • Rosario venoso definido en dos o más cuadrantes
Rol de la TCO en el diagnóstico del EMD
El rápido desarrollo y mejoras de la instrumentación de la TCO contribuyeron aún más con el uso generalizado de la tecnología.68,77 Los primeros sistemas de TCO usan detección por dominio de tiempo (DT), en la que la posición en espejo de referencia y el retraso se escanean mecánicamente para medir señales en forma secuencial desde distintas profundidades y así producir escaneos axiales.73,76 Más recientemente, la detección de dominio espectral o de Fourier se puso a disposición en el mercado. La TCO de dominio espectral (TCO-DE) usa un interferómetro con un espectrómetro de alta velocidad para medir las señales de luz de todos los retrasos de tiempo de manera simultánea y, por eso, proporciona imágenes axiales de mayor resolución.78-80 La TCO-DE tiene varias ventajas respecto a la TCO-DT, entre las que se incluyen una mejor resolución, mejor velocidad de obtención y reducción de artefactos en movimiento.68,81 No obstante, la mayoría de los estudios en curso todavía están obligados a obtener datos mediante TCO-DT y, actualmente, aún no se ha publicado ningún ensayo grande, prospectivo y multicéntrico que use TCO-DE. Además, DCRC.net tiene términos estandarizados para la tecnología de TCO-DT Stratus (Tabla 1).82
La TCO es un método de diagnóstico no invasivo y sin contacto que usa reflejos de luz infrarroja para producir imágenes de cortes transversales confiables, reproducibles y objetivas de las estructuras retinianas y la interfaz vitreorretiniana.64-67 Desde su presentación a principios de la década de 1990, la TCO aportó nuevas perspectivas acerca de los cambios morfológicos de la retina en pacientes con DM y se convirtió en la herramienta de diagnóstico y pronóstico más importante en el tratamiento de la RD y el EMD.68-75 Su rol en el
Los patrones de TCO comunes en el EMD incluyen: 1) engrosamiento difuso de la retina (presente en casi todos los ojos con EMD), 2) edema macular quístico (identificado entre el 44 % y 47 % de los ojos con EMD) y 3) desprendimiento seroso de retina (presente entre el 3 % y 31 % de los ojos con EMD).83 Además, el umbral clínico
•
RD proliferativa
Anomalías microvasculares intrarretinianas prominentes en ≥1 cuadrantes sin signos de retinopatía proliferativa
Uno o más de los siguientes: neovascularización, hemorragia vítrea/prerretiniana
Wilkinson CP et al. Ophthalmology 2003;110(9):1677-1682.
ojo.61 Como las cámaras de AF estándar suelen captar una imagen transversal a 30° o 50°, el Estudio de retinopatía diabética (Diabetic Retinopathy Study) desarrolló un protocolo que consta de siete imágenes estándar a 30°.62 El ancho de este juego de imágenes compuesto es de aproximadamente 75°. No obstante, con frecuencia ocurren isquemia diabética y ausencia de perfusión en la periferia media63 que pueden pasar desapercibidas en una angiografía tradicional. Las técnicas de imaginología con fluoresceína de ángulo ancho captan imágenes del fondo de hasta 200° de amplitud, permitiendo la detección de anomalías periféricas, tales como ausencia de perfusión periférica o pérdidas desde los vasos periféricos.59,61 Esto podría permitir un abordaje láser más dirigido y gradual que minimice los efectos adversos inducidos por el láser, como p. ej., pérdida de campo visual y edema macular.59 Se justifica una mayor exploración del significado de los signos retinianos periféricos detectados por una angiografía panorámica.
26
EMD incluye la evaluación del grosor de la retina, el edema macular quístico, exudados intrarretinianos y líquido subrretiniano.71,72 Por medio de una revisión sistemática de bibliografía que compara la TCO con las pruebas de diagnóstico tradicionales (fotografía estereoscópica de fondo de ojo o biomicroscopía) se llegó a la conclusión de que la TCO funciona bien en el diagnóstico del EMD.74 La TCO también es importante en el control de la respuesta al tratamiento y ha sido aceptada en forma unánime por la red de investigación clínica sobre retinopatía diabética (Diabetic Retinopathy Clinical Research Network - DRCR.net) en sus estudios que involucran diagnóstico, tratamiento y seguimiento de pacientes con EMD.68,75,76
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
para un cambio de grosor en TCO es, en general, >11 % porque la variabilidad de las mediciones por TCO del grosor de la retina han demostrado ser <11 % en diabéticos, independientemente de la presencia o ausencia de EMD.84,85 La TCO con profundidad de imagen mejorada (TCO-PIM) se usa para ver la coroides.86 Esto es importante, porque el grosor de la coroides está estrechamente relacionado con la etapa de la RD y con el grado o tipo de EMD. El engrosamiento progresivo de la capa coroides que ocurre con la evolución de la RD o el desarrollo de EMD puede reflejar la evolución concurrente de la coroidopatía diabética. Por consiguiente, la TCO-PIM es una tecnología no invasiva que permite evaluar con precisión los cambios vasculares coroidales en pacientes diabéticos. A tener en cuenta •
Aún no se ha establecido la relación entre la ausencia de perfusión periférica y el EMD.
•
La AF panorámica es una estrategia de imaginología que recién está surgiendo. Ofrece más información en comparación con la técnica tradicional, pero es cara y requiere de mucho tiempo.
•
La AF panorámica podría mejorar la eficacia del tratamiento láser, ya que tiene la capacidad de detectar con mayor exactitud las áreas periféricas que necesitan tratamiento.
•
•
Los ensayos clínicos que condujeron a la aprobación de las terapias actuales para el EMD aplicaron la TCO-DT como una de las medidas de los criterios de valoración. Por ende, en la actualidad, la TCO-DT debería ser suficiente para tomar decisiones acerca del tratamiento del EMD. No obstante, la TCO-DT depende de la destreza del operador (la mayoría de los ensayos clínicos que emplearon TCODT usaron centros de lectura), y la TCODE causa menos errores relacionados con el operador.81 La TCO-DE se puede usar como herramienta de pronóstico, ya que proporciona más detalles acerca de la ubicación y el subtipo de lesiones.81 Hay algunas indicaciones de que una
coroides más fina podría ser un marcador de mayor riesgo de evolución de la enfermedad. •
La TCO-PIM es una herramienta prometedora, pero aún se encuentra en etapa de exploración. Hay algunas indicaciones que apoyan la relación del grosor de la coroides con la evolución del EMD.
Recomendaciones por consenso 7.
La AF sigue siendo una herramienta importante para evaluar el área de pérdida y guiar las decisiones terapéuticas en pacientes con EMD. [Nivel 158,60,62]
8.
Si bien podría ser útil para la evaluación de pacientes que no responden al tratamiento, la AF de campo ampliado no es necesaria para el manejo adecuado de los pacientes con EMD. [Nivel 3/Consenso]
9.
Como la TCO puede medir objetivamente el grosor de la retina, se considera una herramienta importante y debe usarse en el diagnóstico y el tratamiento del EMD. [Nivel 174,76,82] Lo ideal es que se use la TCO-DE porque brinda una mayor perspectiva de la morfología de la retina. [Nivel 3/Consenso]
Clasificación de la RD y el EMD La clasificación de la evolución natural de la RD es fundamental para la toma de decisiones clínicas y para la comunicación entre colegas y especialidades médicas. La clasificación original de la RD fue descrita en el Simposio de Airlie House en 1968.87 Desde entonces, se han desarrollado varios sistemas de clasificación modificados y se han integrado en las pautas publicadas.88-90 Estos sistemas de clasificación, usados para calificar fotografías de fondos de ojo, se basan en la comprensión de la evolución natural de la RD obtenida a partir del ETDRS. La clasificación del ETDRS se considera la regla de oro para uso en estudios clínicos y epidemiológicos.89 No obstante, la aplicabilidad del sistema de puntuación del ETDRS Tabla 3. Escala de gravedad del edema macular diabético (EMD)
Nivel de gravedad Hallazgos observables en propuesto de la oftalmoscopía con dilatación* enfermedad
EMD aparentemente ausente
Sin engrosamiento de retina aparente ni exudados duros en el polo posterior
EMD leve
Algo de engrosamiento de retina o exudados duros en el polo posterior, pero distantes del centro de la mácula
EMD moderado
Engrosamiento de retina o exudados duros cerca del centro de la macula, sin afectarlo
EMD grave
Engrosamiento de retina o exudados duros que afectan el centro de la mácula
* Los exudados duros son un signo de edema macular actual o anterior. El EMD se define como un engrosamiento de retina que requiere de una evaluación tridimensional que se realiza de la mejor manera a través de un examen con dilatación con biomicroscopía con lámpara de hendidura y/o fotografía estereoscópica de fondo de ojo. Usado y adaptado con autorización de Wilkinson CP, et al. Ophthalmology 2003;110(9):1677-1682.
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
27
A tener en cuenta
Algoritmo III Tratamiento del edema macular subclínico
•
En cuanto al tratamiento del EMD, es importante evaluar si el edema es difuso o focal, central o periférico, y evaluar la proliferación y la tracción. La futura clasificación del EMD debe tener en cuenta estas características de la enfermedad.
•
Las clasificaciones del EMD también deben incluir un pronóstico y el riesgo de evolución, sobre la base de los cuales los médicos tratantes podrán programar seguimientos adecuados y oportunos de sus pacientes.
Paciente diabético con visión funcional relativamente buena (20/25) y evidencia TCO de edema macular subclínico (es decir, un quiste)
El paciente se queja de disminución de visión y pregunta sobre las opciones terapéuticas SI
NO
Tener en cuenta iniciar anti-VEGFd
Tener en cuenta el abordaje de “observar y esperar” con una evaluación luego de 2 meses.d
Es preciso aplicar el criterio clínico. Una angiografía con fluoresceína podría ayudar a definir las razones de la disminución de visión. Actualmente, el ranibizumab es el único tratamiento anti-VEGF aprobado para el EMD.
d
Si los quistes no se resuelven, tener en cuenta iniciar anti-VEGF pese a la ausencia de síntomas, ya que los quistes podrían dañar la retina a largo plazo.
en la práctica clínica diaria está limitada debido a sus varios niveles de gravedad, las reglas de puntuación complicadas y la necesidad de correlación con las imágenes retinianas estándar.90 Estos requisitos suelen ser innecesarios en la práctica diaria y la atención del paciente. La Escala internacional de gravedad clínica de la retinopatía diabética (International Clinical Diabetic Retinopathy Disease Severity Scale), publicada en 2003, ha sido adoptada por varias pautas clínicas internacionales.90 Esta nueva clasificación internacional incorpora evidencia de la evolución de la enfermedad a partir del ETDRS y, según los cambios en la retina, estratifica la RD en cinco niveles de gravedad. Ellos incluyen: 1) sin RD aparente, 2) RD no proliferativa leve, 3) RD no proliferativa moderada, 4) RD no proliferativa grave y 5) RD proliferativa (Tabla 2). La Escala internacional de gravedad clínica del edema macular diabético (International Clinical Diabetic Macular Edema Disease Severity Scale) también es fácil de usar. El primer paso es evaluar la presencia o ausencia de EMD. Si hay EMD se puede categorizar como leve, moderado o grave (Tabla 3).90 Estos sistemas internacionales de clasificación han obtenido el apoyo de la mayoría de las autoridades internacionales, incluyendo la Organización Mundial de la Salud, como sistemas estándar para orientar la práctica basada en la evidencia. Si bien estas clasificaciones no han sustituido al ETDRS, han demostrado ser guías útiles para evaluar a las poblaciones y para facilitar un tratamiento a tiempo. 28
Recomendación por consenso 10. Las clasificaciones internacionales son más aplicables a la práctica clínica diaria, en especial al tratamiento de la RD, que las clasificaciones del ETDRS. Por consiguiente, deben usarse hasta que estén disponibles las clasificaciones con nuevos parámetros obtenidas por nuevas técnicas de diagnóstico por imaginología. [Nivel 3/Consenso] Modalidades de Tratamiento No Farmacológico Fotocoagulación con láser: fortalezas y limitaciones
Historia de fotocoagulación con láser El conocimiento del efecto de la fotocoagulación en los ojos se remonta al año 400 A.C., cuando el filósofo griego Sócrates notó que un eclipse quemaba la retina.91 Inspirado por los efectos que el avistamiento sin protección del eclipse solar de 1945 causó en la mácula de un estudiante de medicina, el oftalmólogo alemán Gerhard Meyer-Schwickerath se convirtió en el pionero de la coagulación de la retina mediante la luz.92 Los primeros fotocoaguladores de arco de xenón produjeron luz compuesta de varias longitudes de onda dentro de los espectros visible e infrarrojo.93 Estos instrumentos carecían de precisión, requerían de un largo período de exposición, causaban dolor y provocaban múltiples complicaciones. Su aplicación resultó en quemaduras de todo el grosor de la retina más que en quemaduras específicas de tejidos.94 El primer láser fue el láser de rubí, inventado por Maiman en 1960.91 Era más compacto y confiable que sus antecesores y resultó eficaz en el control de la RD proliferativa (RDP) en algunos ensayos clínicos. La introducción del láser de argón, en 1968, condujo al uso generalizado de la fotocoagulación oftálmica con láser.95 La longitud de onda ideal empleada para la fotocoagulación de la retina se caracteriza por una buena penetración a través de la absorción media y máxima en el tejido que recibe el tratamiento.91,96 El láser de argón azul verdoso (70 % azul 488 nm, 30 % verde 514,5 nm) fue el láser oftálmico predominante durante muchos años. Sin embargo, debido a varias desventajas, fue posteriormente sustituido por láser verde y amarillo.91,97,98
Evidencia clínica clave para RD y EMD El estudio sobre retinopatía diabética (Diabetic Retinopathy Study – DRS),99 referencia en este campo de especialización y llevado a cabo a mediados de la década de 1970, demostró
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
una reducción del 50 % del riesgo de pérdida de visión grave en ojos con RDP o RD no proliferativa grave tratada con fotocoagulación panretiniana (FPR) en comparación con ojos no tratados. La FPR redujo el riesgo de pérdida de visión grave (definida como AV de 20/800 o peor en dos visitas consecutivas cada cuatro meses) causada por complicaciones de la RDP de 14,0 % a 6,2 % durante un período de dos años.99,100 El ETDRS fue el primer ensayo aleatorizado y controlado destinado a examinar la fotocoagulación con láser en el tratamiento del EMD. En el estudio se demostró un riesgo sustancialmente reducido de pérdida de visión moderada (~3 líneas de ETDRS) en pacientes con EMD clínicamente significativo tratados con fotocoagulación focal.17,101 Por medio del análisis del subgrupo con visión peor de 20/40 al inicio demostró que el 40 % de los pacientes mejoró por ≥6 letras después de 3 años.102 La eficacia de la fotocoagulación con láser focal/en rejilla se confirmó además en el ensayo de DRCR.net.103 Durante un período de dos años, el láser fue más eficaz que la triamcinolona intravítrea (1 mg o 4 mg) para la mayoría de los pacientes con EMD; el cambio medio en el puntaje de AV de letras desde el inicio fue de +1 ± 17 en el grupo de láser, -2 ± 18 en el grupo de 1 mg de triamcinolona y -3 ± 22 en el grupo de 4 mg de triamcinolona; P=0,02 para láser contra 1 mg de triamcinolona; P=0,002 para láser contra 4 mg de triamcinolona). Los resultados de la TCO suelen ser equivalentes a los de la AV. Los resultados de este estudio establecieron a la fotocoagulación focal/de rejilla como punto de referencia contra el cual comparar otros tratamientos en ensayos clínicos de EMD.103 No obstante, la fotocoagulación también está asociada con efectos adversos importantes. A fin de ser eficaz, el protocolo de fotocoagulación del ETDRS requiere que, en algunos casos, las quemaduras se sitúen cerca del centro de la mácula. Con el tiempo, estas quemaduras podrían convertirse en áreas de atrofia progresiva.104 La FPR también puede causar trastornos visuales relacionados con la pérdida de función del tejido retiniano quemado, así
Tabla 4. Estudios aleatorizados y controlados que evaluaron la eficacia del ranibizumab en EMD
Estudio
Grupos de estudio y resultados visuales
N
Criterio de valoración
Cambio medio en la AVMC •
Ranibizumab 0.5 mg: +7.2 letras (P=0.01 vs. solo láser)
•
Láser focal/de rejilla: -0,4 letras
READ-251
•
Ranibizumab 0,5 mg + láser focal/de rejilla: +3,8 letras
(Fase 2)
Aumento medio de la AVMC
126
101
RESOLVE52 (Fase 2)
•
Ranibizumab 0,5 mg: +7,7 letras
•
Láser focal/de rejilla: +5,1 letras
•
Ranibizumab 0,5 mg + láser focal/de rejilla: +6,8 letras
6 meses
24 meses
Cambio en la AVMC desde el inicio 151
•
Ranibizumab (0,3 y 0,5 mg)*: +10,3 letras (P<0,0001)
•
Intervención simulada (láser): -1,4 letras
12 meses
Cambio medio en AVMC RESTORE53 (Fase 3)
345
•
Ranibizumab 0,5 mg: +6,8 letras (P=0,0001 x solo láser)
•
Láser focal/de rejilla: +0,9 letras
12 meses
•
Ranibizumab 0,5 mg + láser focal/de rejilla: +6,4 letras (P=0,0004 x solo láser) Cambio medio en la AV
DRCR.net54 (Fase 3)
854
•
Ranibizumab 0,5 mg + láser inmediato: +9 letras (P<0,001 x intervención simulada)
•
Ranibizumab 0,5 mg + láser diferido: +9 letras (P<0,001 x intervención simulada)
•
Triamcinolona 4 mg + láser inmediato: +4 letras
12 meses
•
Intervención simulada + láser inmediato: +3 letras Cambio medio en la AV • DRCR.net55
361
Ranibizumab 0,5 mg + láser diferido: +9,7 letras (P=0,02)
3 años
•
Ranibizumab 0,5 mg + láser inmediato: +6,8 letras Aumento de ≥15 letras RISE50
377
•
Ranibizumab 0,3 mg: 44,8 % (P<0,0001 x intervención simulada)
•
Ranibizumab 0,5 mg: 39,2 % (P<0,001 x intervención simulada)
3 años
• Intervención simulada: 18,1 % Aumento de ≥15 letras RIDE50
382
•
Ranibizumab 0,3 mg: 33,6 % (P<0,0001 x intervención simulada)
•
Ranibizumab 0,5 mg: 45,7 % (P<0,0001 x intervención simulada)
•
Intervención simulada: 12,3 %
3 years
* Datos combinados AVMC= Agudeza Visual Mejor Corregida
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
29
Algoritmo IV Tratamiento del edema macular de significación clínica sin tracción vitreomacular 1.Engrosamiento de retina a 500 μm del centro de la fóvea o dentro de ese valor 2.Exudados duros a 500 μm del centro de la fóvea, o dentro de ese valor, asociados con engrosamiento de la retina 3.Engrosamiento de la retina en un área de tamaño de 1 disco, dentro del diámetro de 1 disco del centro de la fóvea Fáquico
Con engrosamiento macular central
Pseudofáquico
Tener en cuenta angiografía con fluoresceína Para evaluar la perfusión y ayudar a definir la pérdida como focal o difusa Edema difuso
Tener en cuenta anti-VEGF
Edema focal
Tener en cuenta el láser focal Hay que tener en cuenta los efectos del láser a largo plazo (p. ej., cicatrices)
Tener en cuenta esteroides intravítreos si no se logran los resultados deseados con un anti-VEGF y el paciente corre bajo riesgo de padecer glaucoma
3 - 4 inyecciones mensuales anti-VEGF Evaluar presencia de líquido en la TCO después de 3 meses y obtener angiografía luego de 6 meses SI
SIN líquido + mejoría de la visión
Líquido intrarretiniano leve en la TCO + visión estable
Seguir tratando siempre que haya una mejoría en la TCO y la visión sea estable
Tener en cuenta monitoreo mensual + prn
Tener en cuenta control y tratamiento mensual si no mejorara el líquido
Cuando ya no haya mejoría
Si reapareciera un volumen significativo de líquido, tener en cuenta volver a tratar Es preciso aplicar el criterio clínico.
Realizar angiografía y tener en cuenta lo siguiente: 1. Cerrar el control (si hubiera una mejoría satisfactoria) 2. Esteroides intravítreos (en especial si fallan otros tratamientos) 3. Vitrectomía y “peeling” de membrana si hubiera tracción macular Es preciso aplicar el criterio clínico
como también defectos del campo visual periférico, reducción de la visión nocturna, disminución de la visión de colores y sensibilidad al contraste reducida.105 Además puede contribuir con el desarrollo o la evolución del EMD, hemorragia vítrea y desprendimiento de retina por tracción.106,107 En un intento de reducir estos efectos adversos, muchos especialistas en retina usan actualmente una técnica de ETDRS modificada (mETDRS).108,109 La técnica de mETDRS aplica quemaduras más leves y menos intensas que las especificadas originalmente en el protocolo del ETDRS.109 No obstante, hay que tener en cuenta que nunca se llevó a cabo un ensayo directo para comparar el ETDRS con el mETDRS. Un abordaje alternativo (rejilla macular leve [RML]) que implica la aplicación de quemaduras leves y con amplio espacio entre sí en la macula, evitando la región foveal, fue sometido a prueba contra el mETDRS.109 Doce meses después del tratamiento, la técnica de RML resultó menos eficaz en la reducción del engrosamiento de retina medido por TCO que el actual abordaje de mETDRS de fotocoagulación con láser. Los algoritmos II, IV y V presentan las recomendaciones 30
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
acerca del uso del láser en el tratamiento de la RD y el EMD. El láser de escaneo por patrones (patterned scanning laser – PASCAL) y el láser de diodos con micropulsos de subumbral son las dos innovaciones más recientes para minimizar la formación de cicatrices. Hasta ahora estos nuevos abordajes parecen eficaces, pero se necesita una experiencia a largo plazo para definir sus roles exactos en el tratamiento del EMD. El fotocoagulador PASCAL (532 nm), presentado en 2005, aplica rápidamente quemaduras en una secuencia predeterminada, dispuestas en patrones de múltiples puntos.110 La duración de los pulsos se reduce a 10 - 30 mseg. Según una serie de casos retrospectivos y de observación de 313 pacientes tratados entre 2006 y 2008, el láser de escaneo por patrones es comparable a los protocolos de láser estándar convencionales utilizados para el tratamiento de trastornos retinianos vasculares.111 El estímulo fototérmico puede lograrse usando un láser de micropulsos o PASCAL y está diseñado para apuntar al epitelio pigmentario de la retina con energía subletal, a la vez que minimiza los efectos térmicos negativos sobre la retina. El láser de diodos con micropulsos ha demostrado ser tan eficaz como la fotocoagulación estándar con láser de argón en la reducción del EMD a la vez que admite, potencialmente, una administración más frecuente.112 Esta nueva tecnología se ha evaluado en varios ensayos clínicos113-115 y series de casos.116-118 En 2009, Figueira et al113 compararon la eficacia y los efectos adversos de la fotocoagulación con láser verde convencional y con láser de diodos con micropulsos de subumbral para el edema macular clínicamente significativo. No hubo diferencias estadísticamente significativas en la AV mejor corregida (AVMC), la sensibilidad al contraste y el grosor de la retina entre las dos modalidades de láser a los 0, 4 y 12 meses. Las cicatrices producidas por el láser fueron mucho menos visibles con el láser de diodos con micropulsos de subumbral en comparación con el láser verde convencional. En otro ensayo clínico prospectivo, aleatorizado, controlado y doble ciego, la técnica de láser de diodos con micropulsos de subumbral de 810 nm aplicado en una configuración de alta densidad fue superior a la fotocoagulación estándar del mETDRS durante al menos
un año de seguimiento.25 Además, fueron significativamente más ojos los que recuperaron un grado de visión sustancial y menos los que lo perdieron. Se debe tener en cuenta además que el protocolo estándar para titulación y selección de energía para estos abordajes de fotocoagulación aún está por desarrollarse. A tener en cuenta •
La regresión de la neovascularización posterior a la fotocoagulación lleva tiempo (de dos a tres meses). Durante este tiempo, los médicos podrían tener en cuenta una terapia anti-VEGF.
•
Es preciso tener en cuenta la función visual y el campo visual al evaluar la enfermedad ocular diabética y la respuesta al tratamiento.
•
El tratamiento con láser es difícil de administrar, ya que implica el uso de una rejilla y requiere de cálculos para aplicar el número adecuado de quemaduras, en especial cuando se usa una modalidad de baja intensidad. Estos varios factores a tener en cuenta ante el uso de fotocoagulación en el tratamiento de la RD y el EMD en la práctica clínica derivan en una variación significativa de los resultados visuales.
•
Es probable que en el futuro el tratamiento de la RD y el EMD incluya una combinación de fotocoagulación y terapia anti-VEGF.
Recomendaciones por consenso 11. La FPR sigue siendo la regla de oro para la prevención de la proliferación en RD de alto riesgo (Algoritmo II). [Nivel 117,101-103] 12. La evidencia actual indica que para el tratamiento del EMD el láser no es superior a la terapia anti-VEGF. Los algoritmos IV y V presentan las recomendaciones para el uso del láser en el tratamiento del EMD. [Nivel 3/Consenso] Rol de la vitrectomía en el tratamiento del EMD Las indicaciones principales para la vitrectomía incluyen tracción de la hialoides posterior y EMD difuso que no responde
a los tratamientos convencionales con láser o abordajes farmacológicos, solos o combinados.119-122 El algoritmo VII presenta la recomendación para el uso de la vitrectomía en el tratamiento del EMD. Lewis et al.123 sugirieron en 1992 que la vitrectomía puede resultar en una mejor función visual en ojos con tracción de la hialoides posterior. Se ha formulado la hipótesis de que, en estos casos, la vitrectomía alivia la tracción sobre la mácula generada por el humor vítreo y, por consiguiente, también reduce el edema. En dos estudios realizados a principios de la década del 2000 se demostró que la vitrectomía con “peeling” de la membrana epirretiniana (MER) reduce el edema y mejora la AV.124,125 Además, el resultado del procedimiento no dependió de la presencia o ausencia de desprendimiento de vítreo posterior y MER.124 No obstante, los investigadores notaron que la reducción posoperatoria del grosor de la retina no se completó hasta cuatro meses después del procedimiento. Además, como la vitrectomía podría estar asociada con complicaciones graves, sugirieron exámenes preoperatorios y posoperatorios cuidadosos. En un estudio más reciente realizado en 87 pacientes en nombre de DCRC. net, la vitrectomía produjo resultados mezclados.118 Si bien hubo una reducción del 50 % del engrosamiento de retina en el 68 % de los pacientes, y el 38 % de los pacientes tuvieron una mejoría de ≥ 10 letras en la AVMC, la AV disminuyó en ≤10 letras en el 22 % de los pacientes. Sobre la base de estos resultados, los autores estimaron que entre el 28 % y el 49 % de los ojos con EMD y tracción Algoritmo V
Tratamiento del Edema Macular de Significación Clínica sin Tracción Vitreomacular Sin evidencia de engrosamiento macular central
Láser focal o anti-VEGF
Reevaluación clínica +/- TCO 3 meses después del tratamiento
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Recomendaciones por consenso
Algoritmo VI
Tratamiento del Edema Macular de Significación Clínica con Tracción Vitreomacular
13. Debe tenerse en cuenta una vitrectomía ante la presencia de tracción macular (Algoritmo VII). [Nivel 2119-122]
Con evidencia de engrosamiento vitreomacular por tracción
14. También podría pensarse en la posibilidad de una vitrectomía si el edema no responde a la farmacoterapia (Algoritmo VII). [Nivel 3/Consenso]
Pueden tenerse en cuenta los anti-VEGF
Si hubiera tracción en la TCO, tener en cuenta una vitrectomía
Si hubiera tracción persistente o grave, tener en cuenta una cirugía de vitrectomía vitreomacular tendrán algún grado de mejoría visual, mientras que entre el 13 % y el 31 % tendrán una reducción en la visión.119 Los resultados de varios estudios que evaluaron el efecto de la vitrectomía con MLI demostraron que la vitrectomía con “peeling” reduce el grosor de la retina pero no mejora significativamente la AV.126-128 En un estudio retrospectivo reciente que incluyó 32 ojos se sugirió que los focos hiperreflectivos preoperatorios en las capas exteriores de la retina detectados mediante TCO-DE podían predecir el daño fotorreceptor y un peor pronóstico después de una vitrectomía para el EMD.129 La evaluación de la membrana limitante externa (MLE) antes de la operación predice con mayor precisión la mejora de la visión que la unión fotorreceptora de los segmentos interno y externo (SI/ SE) y el grosor macular central en ojos con EMD. Por consiguiente, la evaluación de la MLE podría permitir a los médicos valorar los resultados de una vitrectomía. En resumen, la etapa del EMD parece de particular importancia para los resultados de la vitrectomía. La evidencia clínica no es sólida pero muestra beneficios en casos seleccionados. A tener en cuenta •
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Es difícil determinar si el edema es la causa de la exudación o la consecuencia de una reacción inflamatoria.
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
Modalidades de Tratamiento Farmacológico Terapias anti FCEV
Rol del ramibizumab en el tratamiento del EMD El ranibizumab es un fragmento de anticuerpo humanizado dirigido a todas las isoformas de VEGF-A, elaborado específicamente para uso intravítreo. La eficacia y la seguridad del ranibizumab para el tratamiento del EMD se evaluaron en varios ensayos clínicos aleatorizados y controlados de fase II (READ-251 y RESOLVE52) y de fase III (RESTORE,53 RISE y RIDE50 y DRCR.net54,55) (Tabla 4). En todos los ensayos, el ranibizumab fue superior al grupo de referencia (láser, intervención simulada [“sham”] o esteroides) en la mejoría de los resultados visuales y anatómicos (TCO). También es importante notar que el ranibizumab fue eficaz en la mejoría de la visión independientemente del control glucémico y de los niveles de hemoglobina A1c. No obstante, hay que tener en cuenta que estos ensayos difieren en cuanto a los programas de tratamiento. Los pacientes incluidos en los ensayos RESTORE y DRCR. net recibieron una dosis de carga de tres inyecciones mensuales, seguida del control mensual y tratamiento según sea necesario (pro re nata [prn]) conforme al protocolo del estudio. Los pacientes que participaron en los ensayos RISE y RIDE recibieron inyecciones continuas de ranibizumab durante tres años. La evidencia más reciente de los ensayos RISE, RIDE y DRCR.net también sugiere que los pacientes con EMD tratados con ranibizumab tienen un riesgo significativamente inferior de
desarrollar RDP que los que recibieron la intervención simulada.56,57 El tratamiento con ranibizumab también parece impedir la evolución de las retinopatías existentes, lograr una regresión de dos pasos en las etapas de la RD en un tercio de los pacientes y mejorar los resultados visuales y anatómicos en estos pacientes.
Rol del bevacizumab en el tratamiento del EMD La evidencia del bevacizumab intravítreo (1,25 mg o 2,5 mg) para el tratamiento del EMD proviene de pequeños ensayos clínicos y estudios de casos retrospectivos.131-135 Esto conlleva varias limitaciones significativas que deben tenerse en cuenta al interpretar los datos. El estudio de tratamiento con bevacizumab o láser ((Bevacizumab or Laser Therapy – BOLT)) es en la actualidad el ensayo más grande disponible y ofrece el mayor nivel de evidencia sobre bevacizumab en el tratamiento del EMD.136,137 El BOLT fue un ensayo de fase II, unicéntrico, de dos años de duración, en el que se compararon los efectos del tratamiento intravítreo con bevacizumab con los del tratamiento con láser reiterados en 80 pacientes con EMD persistente que les causó un perjuicio visual moderado.136 Los resultados a dos años demostraron una ganancia media de +8,6 letras en pacientes tratados con bevacizumab comparados con -0,5 letras con láser.137 La proporción de pacientes que ganaron ≥10 letras fue significativamente superior para el bevacizumab que para el láser (49 % contra 7%, P= 0,001). Además, ningún paciente tratado con bevacizumab perdió ≥15 letras, mientras que un 14 % de los pacientes en el grupo de láser sostuvo una pérdida de letras de ≥15 (P= 0,03). En un ensayo aleatorizado prospectivo reciente, a pequeña escala, que incluyó 63 ojos con EMD de afectación central, se comparó el bevacizumab intravítreo (1,5 mg) con el ranibizumab (0,5 mg).138 Si bien a un año ambos agentes mostraron una eficacia similar respecto a la AV y al grosor del subcampo central (GSCC), el tratamiento con ranibizumab condujo a una reducción más rápida del GSCC y a una recuperación más rápida de la AVMC. El número promedio de inyecciones fue mayor en el grupo de bevacizumab.
Rol emergente del aflibercept en el tratamiento del EMD El aflibercept ( VEGF Trap-Eye) es una proteína fusionada dirigida al VEGF-A, al VEGF-B y al factor de crecimiento placentario (FCP).139,140 En el ensayo Da Vinci de fase II, el aflibercept (0,5 mg o 2 mg cada cuatro semanas y 2 mg cada ocho semanas) fue superior al láser en la mejoría de la visión y la reducción del grosor de la retina central (GRC) en las semanas 24 y 52.141,142 En la semana 52, mayores porcentajes de pacientes tratados con aflibercept exhibieron una mejoría de su puntaje de gravedad de la retinopatía diabética (Diabetic Retinopathy Severity Score – DRSS) en comparación con el grupo de láser (31 % - 64 % para los grupos de aflibercept en comparación con 12 % para el láser).142 Además, los ojos tratados con aflibercept tuvieron menor probabilidad de que su DRSS empeorase en comparación con los ojos tratados con láser. Esto sugiere que la actividad biológica del aflibercept no solo trata el EMD sino que también puede disminuir la gravedad de la RD, cambiando por tanto la historia natural de la enfermedad. Los dos ensayos de fase III - VIVID (realizado en EE. UU.) y VISTA (realizado en Europa, Japón y Australia)- confirmaron la superioridad del aflibercept respecto al láser.143 En estos ensayos, se probaron dos dosis de aflibercept: 2 mg cada 4 semanas (c/4 sem.) o cada 8 semanas (c/8 sem.). La dosis c/8 sem. demostró una eficacia similar a la dosis c/4 sem. La mejoría promedio de la AVMC varió entre 10,5 y 12,5 letras. No obstante, el patrón de “sube y baja” del GRC, similar al observado con el mismo esquema posológico en casos de degeneración macular relacionada con la edad (DME),144 sugiere que la dosis c/8 sem. podría ser inferior a lo ideal para algunos pacientes. Además, el número de tratamientos en el ensayo Da Vinci durante la fase de prn fue similar al registrado con ranibizumab en los estudios RESTORE53 y DRCR.net,54,55 lo que indica que el aflibercept no cuenta con la ventaja posológica. También es importante tener en cuenta que, de manera similar al bevacizumab, el aflibercept es un anticuerpo completo y que la porción Fc podría aumentar su exposición sistémica. En los ensayos Da Vinci, VIVID y VISTA, el tratamiento con aflibercept, en general, fue bien tolerado. No hubo diferencia en los eventos adversos
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sistémicos graves, incluyendo eventos cardiovasculares, cerebrovasculares y eventos tromboembólicos vásculo-arteriales periféricos según los criterios del grupo Antiplatelet Trialists’ Collaboration.145,146 Los algoritmos III a IV ilustran el uso recomendado de la terapia anti-VEGF, en particular el ranibizumab, en el tratamiento del EMD. A tener en cuenta •
Deben tomarse en cuenta los signos de edema macular en la TCO al decidir si se va a aplicar el tratamiento o volver a aplicarlo.
•
El programa mensual fijo usado en los ensayos RISE y RIDE produce los mejores resultados. No obstante, este programa está asociado con una carga considerable tanto para pacientes con EMD como para los profesionales médicos tratantes.
•
•
•
El uso simultáneo del láser podría reducir la frecuencia de las inyecciones anti-VEGF, lo que no mejora los resultados visuales. No obstante, aún falta evidencia acerca del momento adecuado para la aplicación del láser en relación con una inyección antiVEGF. En los ensayos clínicos el láser se aplicó tres meses después del inicio del tratamiento con ranibizumab. Las recientes innovaciones en técnicas con láser podrían colaborar aún más con mejores resultados de eficacia y seguridad a la vez que reducen la carga del tratamiento. Al seleccionar el tratamiento para el EMD, los médicos deben tener en cuenta las indicaciones aprobadas en sus respectivos países. Los datos de aflibercept confirman más aún la eficacia de apuntar a la ruta del VEGF en el tratamiento del EMD. Se necesitan datos a largo plazo de los ensayos de fase III para sacar más conclusiones.
Recomendaciones por consenso 15. Los datos disponibles han establecido al ranibizumab, con o sin láser, como la regla de oro para el tratamiento del EMD. El aumento promedio esperado de la visión, sobre la base de la evidencia disponible, es de 34
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
entre ocho y 12 letras. [Nivel 151-55] Los datos de bevacizumab respaldan la evidencia de que la terapia antiVEGF es eficaz en el tratamiento del EMD; pero hay menos evidencia que respalde su recomendación. El ensayo BOLT es el mayor ensayo aleatorizado con bevacizumab para el tratamiento del EMD realizado hasta la fecha. [Nivel 2136,137] Los médicos deben tener presente que el bevacizumab no está aprobado para ser administrado por vía intravítrea y deben asumir la responsabilidad de su uso fuera de las indicaciones de la etiqueta. No obstante, el riesgo de no tratar es más alto que el riesgo de usar el fármaco fuera de las indicaciones de la etiqueta. [Nivel 3/Consenso] 16. Los pacientes con EMD deben recibir inyecciones mensuales de ranibizumab durante al menos tres a seis meses consecutivos (dosis de carga) hasta que el paciente se considere estable. La fase de carga debe ir seguida de visitas mensuales de evaluación (visión, TCO). [Nivel 1124,125,127,128] 17. Los criterios para repetir el tratamiento deben basarse en las características individuales del paciente y en su respuesta al tratamiento. [Nivel 3/Consenso] 18. Se podrá aplicar láser en cualquier momento luego de iniciar el ranibizumab. [Nivel 3/Consenso] Corticosteroides para el tratamiento del EMD Debido a sus propiedades antiinflamatorias y, hasta cierto punto, antiangiogénicas y de antipermeabilidad, el esteroide sintético triamcinolona es considerado una herramienta importante en el tratamiento del EMD.103,147 La primera formulación de triamcinolona disponible en el mercado fue Kenalog®. Su primer uso en oftalmología fue en prevención de la vitreorretinopatía proliferativa luego de una cirugía por desprendimiento de retina.148,149 También se usa, fuera de lo recomendado en la etiqueta, en el tratamiento del EMD.150,151 No obstante, los conservantes en la preparación de Kenalog (es decir, el alcohol bencílico) pueden causar inflamación intraocular (~8 % de los pacientes tratados).150,152-154 Por otra parte, la triamcinolona micronizada (con cristales más
pequeños) sin conservantes (Triesence®, Trivaris®) parece causar menos daño a la neurorretina en comparación con el compuesto regular.155,156
Algoritmo VII - Vitrectomía
La evidencia clínica señaló una notoria mejoría de la AV y reducción del grosor de la retina después de una única dosis de triamcinolona.147 Es más: Gillies et al.157 demostraron la eficacia de la triamcinolona en el tratamiento de EMD resistente al láser. Luego de cinco años, el 42 % de los casos demostraron una mejoría de cinco letras. Otro estudio confirmó que el uso de triamcinolona antes del láser duplica las probabilidades de que la visión mejore en ≥10 letras.158 La incidencia de hipertensión ocular (~25 % de los pacientes experimentan un aumento temporal de la presión intraocular) y cataratas (con una dosis de 4 mg en el 83% de los pacientes en tres años) podría ser un problema. Es importante tener en cuenta que el ensayo DRCR.net estableció la superioridad del láser sobre la triamcinolona.103 No obstante, no se observó ninguna diferencia en el aumento de la visión en ojos pseudofáquicos tratados con ranibizumab o triamcinolona en un subanálisis de este ensayo.54 Recientemente se evaluaron dos implantes de esteroides en el tratamiento del EMD.159,160 Ozurdex® es un implante biodegradable de dexametasona de administración lenta que se inyecta en el humor vítreo. Se observó la superioridad de Ozurdex respecto a la intervención simulada más láser durante los primeros nueve meses posteriores al procedimiento, pero no hubo una diferencia significativa entre grupos de tratamiento a un año.159 Además, fueron necesarios cinco procedimientos en el transcurso de tres años para controlar el edema. En un ensayo de fase II que incluyó 55 ojos vitrectomizados, la reducción del grosor macular central y la mejoría de la visión duraron seis meses.160 Esto sugiere que Ozurdex® podría ofrecer una margen de oportunidad en estos pacientes durante la cual podría mejorarse la eficacia de otras modalidades terapéuticas. Iluvien®, un implante de 25 mg que contiene 190 µg de fluocinolona, ha sido aprobado recientemente en Europa a continuación de los resultados del ensayo FAME.161 En un programa de tratamiento reiterado de 12 meses y con la capacidad de usar láser seis semanas después del implante y cada tres meses de ahí en adelante, Iluvien fue superior a las inyecciones de intervención simulada a tres años.
Vitrectomía
Como los esteroides solo tienen efectos antiangiogénicos secundarios, solo tratan una parte de la patología del EMD.
•
Los beneficios asociados con los esteroides se ven empañados por preocupaciones sobre temas tales como la hipertensión ocular y el desarrollo de cataratas.
•
El seguimiento frecuente requerido luego del implante de Ozurdex representa una carga significativa tanto para el médico como para el paciente. Además, los efectos de los esteroides comienzan a desaparecer luego de dos meses. Por eso, este abordaje terapéutico está asociado con “mucho trabajo y pocos beneficios”.
Desprendimientos por tracción
Hemorragia en humor vítreo que desaparece pero reaparece con frecuencia
Desprendimiento regmatógeno por tracción
Tener en cuenta inhibidores de VEGF antes de la operación para reducir la hemorragia (si no hay elementos de tracción; evitar si hubiera fibrosis o contracción significativas)
Desprendimiento macular por tracción
Se requiere del criterio clínico cuando se tiene en cuenta un anti-VEGF preoperatorio Tener en cuenta inhibidores de VEGF después de la operación para reducir la hemorragia y las complicaciones asociadas con la vitrectomía
20. La rápida reducción del edema que se logra con los esteroides ofrece una margen de oportunidad para el uso de otros abordajes terapéuticos como el láser o la terapia anti-VEGF. [Nivel 2160] 21. Los esteroides podrían tenerse en cuenta para pacientes pseudofáquicos (Algoritmo IV). [Nivel 254] Distinción entre pacientes que responden y no responden al tratamiento A tener en cuenta: •
La duración del edema se puede usar como elemento de predicción de la respuesta al tratamiento: cuanto más dure el edema, peor será el resultado.
•
Para definir a los pacientes que no responden al tratamiento, podrá tenerse en cuenta el protocolo del DCRC.net.
•
Para controlar la respuesta de los pacientes al tratamiento, es preferible emplear la tabla del ETDRS antes que la tabla de Snellen.
A tener en cuenta: •
Hemorragia Hemorragia en humor vítreo que no desaparece
Recomendaciones por consenso
Recomendación por consenso
19. Como la mejoría inicial de la visión y la reducción del edema obtenidas con los esteroides no se mantienen, no se deben usar esteroides como monoterapia sino en combinación con otras modalidades terapéuticas. [Nivel 3/Consenso]
22. Si bien se considera que un paciente con una clara mejoría en la visión y en la anatomía respondió al tratamiento, un paciente sin cambios en la AV
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después de tres a seis meses de inyecciones mensuales anti-VEGF ni cambios en la TCO (se espera una mejoría de al menos 30-50 µm luego de una segunda inyección) deberá considerarse como paciente que no responde al tratamiento. Para este paciente deberá tenerse en cuenta un cambio en el tratamiento. [Nivel 3/ Consenso] Seguridad de las farmacoterapias en el tratamiento del EMD Las diferencias en la estructura molecular de tres agentes antiVEGF eficaces en el tratamiento del EMD se reflejan en sus propiedades farmacológicas que podrían dar cuenta de las diferencias en sus perfiles de seguridad.162-166 El ranibizumab, un fragmento de anticuerpo de aproximadamente 48 dDa, fue diseñado específicamente para uso intravítreo.130,167 El bevacizumab y el aflibercept, por otra parte, son anticuerpos completos inicialmente desarrollados para la administración intravenosa en pacientes oncológicos.168,169 Si bien la eliminación sistémica del ranibizumab después del uso intravítreo es de aproximadamente dos horas,167 la eliminación sistémica del aflibercept y del bevacizumab es significativamente más larga: cuatro a cinco días para el aflibercept139,170 y alrededor de 20 días para el bevacizumab.169 El transporte desde el ojo a través de la barrera hematorretiniana hacia la circulación sistémica se atribuye al fragmento Fc de la molécula y sus receptores expresados en múltiples tejidos oculares.171,172 La afinidad para el VEGF también difiere entre tratamientos anti-VEGF intravítreos.173 El ranibizumab tiene una alta afinidad para el VEGF-A y el aflibercept para el VEGF-A, VEGF-B y PGF.174,175 Aún no está claro qué rol podría representar el amplio espectro de afinidad del aflibercept fuera del ojo, en especial dado que los datos más recientes indican un efecto neuroprotector del VEGF-B.176 Como el VEGF representa un papel importante en la angiogénesis, en la
36
reparación vascular y en la homeostasis, su supresión sistémica puede generar posibles efectos nocivos sobre varios sistemas de órganos.177,178 Por ejemplo, se ha demostrado que la supresión del anti-VEGF en pacientes con cáncer conlleva varias consecuencias adversas, como p. ej., problemas de cicatrización de heridas, hipertensión, trombosis arterial, insuficiencia cardíaca, proteinuria y efectos adversos renales.178 Este potencial de afectar la seguridad sistémica es particularmente importante al seleccionar el tratamiento para pacientes diabéticos que ya corren alto riesgo de padecer complicaciones cardiovasculares y renales. Debe notarse que los ensayos clínicos que evalúan los tratamientos anti-VEGF de afecciones oculares no se han impulsado para comparar su seguridad sistémica. Como el ranibizumab ha sido desarrollado y aprobado para uso intravítreo y para tratamiento de enfermedades oculares, su perfil de seguridad se ha probado y definido sobre la base de varios ensayos clínicos grandes.179,180 Estos ensayos condujeron posteriormente a la aprobación regulatoria del fármaco para varias afecciones oculares, incluyendo la DME y el EMD. En ensayos clínicos grandes los eventos oculares fueron similares entre la intervención simulada y el ranibizumab. Por otra parte, el uso fuera de lo especificado en la etiqueta y la reconstitución necesaria para preparar bevacizumab para uso intraocular se han vinculado a casos de endoftalmitis bacteriana grave que resultaron en malos resultados visuales.181,182 Por consiguiente, los médicos deben tener en cuenta que el bevacizumab no está aprobado para uso intraocular y, como tal, debe ser reconstituido por una farmacia de manipulación. También se encontraron agregados de alto peso molecular en el bevacizumab reenvasado.183,184 Esto podría conducir a la obstrucción de la salida del humor acuoso y la posterior elevación de la presión intraocular y el glaucoma.185,186 Los índices de eventos cardiovasculares observados en los ensayos clínicos de ranibizumab fueron bajos y estuvieron alineados con los índices observados en la población general.179 Por otra parte, las señales de seguridad de dos grandes ensayos en pacientes con DME sugieren una mayor incidencia de eventos adversos graves, en especial complicaciones gastrointestinales con bevacizumab en comparación con ranibizumab.162,163 Esto tiene un paralelismo con el recuadro de advertencia del bevacizumab intravenoso que incluye la afectación de la cicatrización de heridas y perforación gastrointestinal.169 Se incluye una advertencia similar en la etiqueta de Zaltrap® (formulación intravenosa de aflibercept).186 En resumen, si bien las señales de seguridad de los ensayos clínicos acerca de la administración intravítrea de antiangiogénicos pueden ser pocas, los médicos tratantes deben tener en cuenta que los pacientes de la práctica clínica son diferentes a los incluidos en los ensayos clínicos. Las comorbilidades podrían contribuir aún más con eventos adversos no deseados. Respecto a los esteroides intraoculares, queda bien establecido que su uso conduce al aumento de la presión intraocular, glaucoma y posibles cataratas.157,158,187-189 El láser está asociado con complicaciones en la cicatrización.97,190-192
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
A tener en cuenta: •
El tratamiento de pacientes diabéticos podría ser más difícil que el de los pacientes con DME y oclusión de venas retinianas debido a la naturaleza sistémica de la enfermedad y las comorbilidades asociadas. Recomendaciones por consenso: 23. Los datos de ensayos clínicos grandes establecieron un perfil de seguridad favorable para el ranibizumab. Además, el perfil de seguridad de ranibizumab en el EMD coincide con el observado en los pacientes con DME. [Nivel 1179,180] No obstante, como faltan datos de seguridad para otros antiangiogénicos (bevacizumab y aflibercept), es necesaria una farmacovigilancia. Además, los médicos deben tener presente que el bevacizumab no está indicado para la administración intravítrea. [Nivel 3/Consenso] 24. Como los esteroides intravítreos pueden llevar a un aumento de la presión intraocular, glaucoma y cataratas, es preciso tener precaución y realizar seguimientos frecuentes al paciente [Nivel 1157,158,187-189]. 25. Los médicos deben tener en cuenta que el tratamiento con láser puede producir cicatrices y complicaciones relacionadas. [Nivel 197,190-192] 26. Es preciso tener en cuenta el estado de salud general de los pacientes diabéticos al seleccionar la terapia para el EMD. [Nivel 3/Consenso] 27. Los médicos tienen que asegurarse de aplicar los más altos estándares de asepsia durante el procedimiento de administración. [Nivel 3/Consenso] Cataratas y EMD Los pacientes diabéticos tienen del doble al cuádruple de probabilidades de desarrollar cataratas en comparación con los pacientes no diabéticos.193 El riesgo es mayor en pacientes con RD proliferativa, los mayores de 40 años y pacientes insulinodependientes.194 La relación entre la cirugía de cataratas y la historia natural de la RD no queda clara.
También es incierto hasta qué punto el tratamiento de la RD y del EMD antes de la cirugía de cataratas afecta su resultado. Las tres situaciones principales a tener en cuenta incluyen: •
Pacientes en necesidad de cirugía de cataratas sin necesidad de tratamiento para retinopatía.
•
Se ha demostrado que los pacientes con retinopatía preexistente corren un mayor riesgo de evolución de la retinopatía, desarrollo de edema macular y pérdida de visión en comparación con los que no tienen retinopatía preexistente195
•
Pacientes que necesitan cirugía de cataratas y vitrectomía
•
Si bien varios estudios han demostrado que el pronóstico visual es similar cuando se realizan ambos procedimientos simultáneamente, desde el punto de vista del paciente es preferible realizar los procedimientos en secuencia196,197
•
Pacientes con cristalino limpio que necesitan una vitrectomía pero no una cirugía de cataratas
En todos los casos, es fundamental una evaluación preoperatoria que debe incluir una evaluación de AV, evaluación de fondo de ojo, una TCO y una ecografía. Si bien las causas de edema macular posterior a una cirugía de cataratas no se han comprendido en su totalidad, se sospecha que las citocinas inflamatorias, los mediadores vasoactivos y la tracción de la membrana hialoidea podrían tener algo que ver.198 Como el VEGF contribuye con una serie de cambios fenotípicos observados en el edema macular,199 se demostró en estudios recientes que el uso de antiangiogénicos intravítreos combinados con facoemulsificación pueden prevenir el desarrollo de EMD posoperatoria luego de una cirugía de cataratas.200-206 A tener en cuenta: •
No está claro si el edema posterior a una cirugía de cataratas en pacientes diabéticos es un “verdadero” EMD o solo un edema posquirúrgico que puede tratarse con gotas oftálmicas antiinflamatorias no esteroideas.
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
37
•
•
•
•
La TCO podría ser útil para determinar si el edema se encuentra en la capa nuclear externa o interna. Como el EMD suele afectar la capa externa, ella podría utilizarse como guía de las opciones terapéuticas. El anti VEGF preoperatorio podría evitar el desarrollo de edema posquirúrgico, pero la evidencia no es sólida. Los quistes retinianos grandes deben tratarse antes de la cirugía de cataratas, ya que podrían romperse durante el procedimiento y dañar la retina.
Recomendaciones por consenso 28. El primer paso del tratamiento de un edema tras una cirugía de cataratas en pacientes diabéticos es el abordaje de “observar y esperar” durante uno a dos meses o gotas oftálmicas antiinflamatorias no esteroideas. En caso de edema persistente, se pueden tener en cuenta los antiangiogénicos o los esteroides intravítreos. [Nivel 3/Consenso] 29. El tratamiento de EMD antes de una cirugía de cataratas debe quedar bien documentado. [Nivel 3/Consenso]
30. Los pacientes con EMD deben tener el edema bajo control (tratado, estable y respondiendo al tratamiento) antes de la cirugía de cataratas. [Nivel 3/Consenso]. 31. Si luego de la cirugía de cataratas se desarrollara un edema en el ojo contralateral, deberá examinarse y tratarse de manera independiente. [Nivel 3/Consenso]. Terapias emergentes Como el VEGF representa un importante papel en la patogénesis de la RD y el EMD, aún sigue la investigación que apunta a la ruta de señalización del VEGF (es decir, la degradación del ácido ribonucleico [ARN] mensajero del VEGF usando pequeños ARN interferentes, bloqueo de receptores de VEGF, etc.).207 Además, se están investigando otras citocinas implicadas en la patogénesis de la enfermedad (como p. ej. el factor de necrosis tumoral),208 además de la proteína quinasa C209 y la diana de rapamicina en células de mamíferos210. Entre otras modalidades terapéuticas en las etapas precoces del desarrollo clínico incluyen terapia genética,211,212 tecnología no codificante que utiliza una hebra de oligonucleótidos que se une a un ARN mensajero específico y lo inhibe,213 terapia con péptido de unión a integrinas214 y proteínas de repetición de anquirina diseñadas.215 Además, no se deben pasar por alto otras opciones disponibles al alcance de la mano en casos difíciles, como abordajes quirúrgicos,216,217 nuevas modalidades con láser218 e implantes esteroideos.160 A tener en cuenta: Los antiangiogénicos han puesto el listón muy en alto, lo que dificulta la capacidad de los nuevos tratamientos en alcanzar su misma eficacia, seguridad, practicidad de administración y costo.
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208. Jonas JB, Jonas RA, Neumaier M, Findeisen P. Cytokine concentration in aqueous humor of eyes with diabetic macular edema. Retina 2012;32(10):2150-2157. 209. PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch Ophthalmol 2007;125(3):318-324. 210. Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology 2012;119(1):124-131. 211. Maclachlan TK, Lukason M, Collins M, et al. Preclinical safety evaluation of AAV2sFLT01- a gene therapy for age-related macular degeneration. Mol Ther 2011;19(2):326-334. 212. Campochiaro PA. Gene transfer for neovascular age-related macular degeneration. Hum Gene Ther 2011;22(5):523-529. 213. Hnik P, Boyer DS, Grillone LR, Clement JG, Henry SP, Green EA. Antisense oligonucleotide therapy in diabetic retinopathy. J Diabetes Sci Technol 2009;3(4):924-930. 214. Quiroz-Mercado H, et al. Integrin Peptide Therapy: The Human Experience in DME. Presented at the American Society of Retina Specialists 2012 Annual Meeting. Las Vegas (NV): August 25-29, 2012. 215. Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol 2013;155(4):697-704. 216. McHugh D, Gupta B, Saeed M. Intravitreal gas injection for the treatment of diabetic macular edema. Clin Ophthalmol 2011;5:1543-1548. 217. Stalmans P, Benz MS, Gandorfer A, et al. MIVITRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367(7):606615. 218. Kozak I, Oster SF, Cortes MA, et al. Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology 2011;118(6):1119-1124.
ESTÁNDARES DE BUENAS PRÁCTICAS EN RETINOPATÍA DIABÉTICA
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Definição dos padrões de boas práticas para o diagnóstico
e tratamento da retinopatia diabética e do edema macular diabético na América Latina Schlottmann P.1, Acosta C.2, Alezzandrini A.A.3, Bafalluy J.4, Biccas L.5, Hidalgo Cano6, Damico F.M.7, Dib G.8, Fromow-Guerra J.6, Jorge R.9, Lavinsky D.10, Morales-Canton V.11, Roca J.A.12, Farah *M.E.13
Organización Médica de Investigación, Buenos Aires, Argentina. 2Universidad CES, Medellín, Colombia,3Universidad de Buenos Aires, Argentina, 4Universidad Nacional de Rosario, Rosario, Argentina, 5Clínica Ocular Oftalmologia, Vitória, Brasil, 6Universidad Nacional Autónoma de México, Ciudad de México, México, 7 Universidade de São Paulo, Brasil, 8Universidad del Zulia, Maracaibo, Venezuela, 9Universidade de São Paulo, Ribeirão Preto, Brasil, 10Universidade Federal do Rio Grande do Sul, 11Asociación para Evitar la Ceguera en México, Ciudad de México, México, 12Universidad Peruana Cayetano Heredia, 13 Universidade Federal de São Paulo, Brasil. 1
*Endereço para correspondência: M.E. Farah, mefarah@uol.com.br
Resumo Objetivo: Oferecer recomendações e orientação baseadas em evidências para o tratamento da retinopatia diabética (RD) e do edema macular diabético (EMD) conforme a evidência clínica publicada recentemente e a experiência clínica. Métodos: Foi realizada pesquisa bibliográfica nos bancos de dados PubMed e Cochrane utilizando os termos “edema macular diabético” ou “retinopatia diabética” para identificar os estudos publicados de janeiro de 2008 a novembro de 2013. Posteriormente, procedeu-se pesquisa manual das referências citadas em artigos selecionados, publicados em periódicos científicos especializados. As referências identificadas nessas pesquisas bibliográficas foram revistas e apresentadas pelos membros de uma comissão de peritos em EMD na América Latina a todo o grupo durante o encontro de consenso, de dois dias de duração. Durante a reunião, os especialistas formularam recomendações levando em conta as vantagens, os riscos e os efeitos adversos das intervenções para a saúde. Níveis de evidência foram atribuídos às referências utilizadas para apoiar as recomendações com base no sistema de classificação de evidências SORT (Strength of Recommendation Taxonomy) referente à força da recomendação. Resultados: Foram formuladas 31 recomendações de consenso. Entre elas, a recomendação do controle glicêmico precoce em pacientes diabéticos para reduzir o risco de evolução da doença ocular. O grupo de especialistas também recomendou a coleta de dados epidemiológicos para definir melhor a prevalência da RD e do EMD
44
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
na América Latina e definir algoritmos para o manejo e tratamento nos vários estágios da doença. Foi destacada a necessidade da triagem precoce e o desenvolvimento da infraestrutura para garantir aos que precisam um acompanhamento e tratamento adequados. Para avaliar adequadamente a evolução da doença e a resposta ao tratamento faz-se necessário realizar uma angiografia de fluorescência (AF) e uma tomografia de coerência óptica (TCO). Com base em evidências de alto nível, recomendamos ranibizumabe como o padrão-ouro para o tratamento do EMD e a fotocoagulação panretiniana (FPR) com o padrão-ouro para a RD proliferativa. A vitrectomia deve ser considerada na presença de tração macular ou se o edema não responder à farmacoterapia. Como os esteroides intravítreos dão lugar a uma redução do edema, eles podem ser utilizados para melhorar os efeitos de outros tratamentos, bem como em olhos pseudofácicos. Finalmente, ao selecionar um tratamento para a RD ou o EMD, é de especial importância considerar o estado de saúde geral do paciente. Conclusão: Embora essas diretrizes não pretendam substituir a decisão clínica profissional individual, elas devem ajudar a otimizar o tratamento do EMD na América Latina e garantir que os pacientes recebam a melhor atenção disponível e de maneira oportuna. Introdução O objetivo deste documento é proporcionar orientação a médicos oftalmologistas e especialistas em retina da América Latina com relação ao diagnóstico e tratamento da retinopatia diabética (RE) e o edema macular diabético (EMD). As recomendações descritas foram
desenvolvidas sistematicamente com base em uma profunda análise da bibliografia médica e da experiência clínica. No entanto, essas diretrizes não pretendem substituir a decisão clínica profissional individual, mas prestar informações a respeito dos padrões da prática. Além disso, o presente documento não pode ser utilizado como fonte legal porque não oferece orientação individualizada para todos os pacientes em todas as situações. Na verdade, ao considerar abordagens terapêuticas para pacientes diabéticos com comprometimento ocular, os médicos oftalmologistas devem considerar as necessidades, as preferências, os valores, bem como o contexto econômico e pessoal de cada paciente separadamente, e levar em conta a realidade de seu âmbito de atendimento médico. Sabe-se que existem desequilíbrios nos recursos humanos, econômicos e de atenção médica nos diferentes países e regiões da América Latina e que esses fatores podem afetar as preferências, opções e decisões de médicos e de pacientes. Métodos Foi realizada pesquisa bibliográfica na língua inglesa nos bancos de dados PubMed e Cochrane com os termos diabetic macular edema (edema macular diabético) ou diabetic retinopathy (retinopatia diabética) para identificar os estudos publicados de janeiro de 2008 a novembro de 2013. Posteriormente, procedeu-se pesquisa manual das referências citadas em artigos selecionados, publicados em periódicos científicos especializados. As fontes preferidas foram as meta-análises, os exames sistemáticos e os estudos clínicos
randomizados com pelo menos 1 (um) ano de acompanhamento, publicados nos últimos cinco anos. As referências identificadas pelos pesquisadores de bibliografia foram revistas pelos membros da comissão de especialistas em EMD da América Latina; cada membro era responsável pelo exame das referências correspondentes ao seu tema respectivo para garantir a sua relevância e a adequação da qualidade metodológica utilizada. Os membros da comissão de especialistas também apresentaram evidências-chave para todo o grupo durante a reunião de consenso, de dois dias de duração, que teve lugar em Miami, Flórida, nos dias 13 e 14 de novembro de 2013. Durante a reunião, os especialistas analisaram a evidência e formularam recomendações levando em conta as vantagens, os riscos e os efeitos adversos das intervenções para a saúde. Níveis de evidência foram atribuídos às referências utilizadas para apoiar as recomendações com base no sistema de classificação de evidências SORT (Strength of Recommendation Taxonomy) referente
Apêndice 1. Avaliação da qualidade da evidência – Classificação da força da recomendação (SORT)
Qualidade do estudo
Diagnóstico
Tratamento/ prevenção/triagem
Prognóstico
Nível 1: Boa qualidade, evidência orientada ao paciente
• •
Norma de decisão clínica validada RS/meta-análise de estudos de alta qualidade Estudo de coortes de diagnóstico de alta qualidade*
•
RS/meta-análise ou ERCs com achados coerentes ERC individual de alta qualidade† Estudo “todos ou nenhum”‡
•
Norma de decisão clínica não validada RS/meta-análise de estudos de qualidade inferior ou estudos com achados incoerentes Estudo de coortes de diagnóstico de qualidade inferior ou estudo de controle de caso para diagnóstico
•
RS/meta-análise de estudos clínicos de qualidade inferior ou de estudos com achados incoerentes Estudo clínico de qualidade inferior Estudo de coortes Estudo de controle de casos
•
• Nível 2: Qualidade
limitada,evidência orientada ao paciente
• •
•
Nível 3: outra evidência
• •
• • •
•
•
• •
RS/meta-análise de estudos de coortes de boa qualidade Estudo prospectivo de coortes com bom acompanhamento RS/meta-análise de estudos de coortes de qualidade inferior ou estudos com resultados incoerentes Estudo de coortes retrospectivo ou estudo de coortes prospectivo com acompanhamento deficiente Estudo de controle de casos Série de casos
Diretrizes de consenso, extrapolações de pesquisa em laboratório, prática habitual, opinião, evidência orientada à doença (somente resultados intermédios ou fisiológicos), ou séries de casos para estudos de diagnóstico, tratamento, prevenção ou triagem
* Estudo de coortes de diagnóstico de alta qualidade: projeto de coortes, tamanho adequado, espectro adequado de pacientes, cegamento e um padrão referencial bemdefinido. † ERC de alta qualidade: alocação oculta, cegamento (se possível), análise de intenção de tratar, poder estatístico adequado, acompanhamento adequado (acima de 80%). ‡ No estudo “todos ou nenhum”, o tratamento causa uma alteração drástica nos resultados, como por exemplo, antibióticos para meningite ou cirurgia para apendicite, o que impossibilita realizar estudos em ensaios controlados.
RS = revisão sistemática; ERC = estudo randomizado e controlado Usado e adaptado com autorização de: Ebell MH, Siwek J, Weiss BD, Woolf SH, Susman J, Ewigman B, Bowman M. Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician. 2004;69(3):548-556.
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
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Algoritmo I Triagema para a retinopatia diabética Diabetes tipo 1 diagnosticado depois da puberdade
Diabetes tipo 1 diagnosticado antes da puberdade
Diabetes tipo 2
La evaluación debe iniciarse 5 años después del diagnóstico de diabetes
A triagem deve ser iniciada na puberdade (a menos que existam outras considerações que indiquem a necessidade de um exame precoce)
A triagem deve ser iniciada no momento do diagnóstico
Presença de retinopatia não-proliferativa Leve
Moderada
Grave
Examen anual
Acompanhamento a cada 6 meses
Acompanhamento a cada 3 meses
Presença de retinopatia proliferativa SIM Leve examen anual
NAO Moderada ou grave exame a cada 3 a 6 meses
exame a cada 3 a 6 meses
Os algoritmos são utilizados com permissão dos algoritmos canadenses para o tratamento do EMD (Hooper P. et al. Ophthalmologica. 2014;231(1):2-15). Os algoritmos são modificados posteriormente com permissão para refletir a prática atual e os requisitos dos países latino-americanos. a A avaliação da triagem deve incluir: 1. medição da acuidade visual, 2. pressão intraocular, 3. TCO para avaliar a presença de edema macular, 4. biomicroscopia para avaliar a presença de neovascularização da íris e do ângulo, 5. fotos do fundo de olho para documentar, definir o estágio e comparar a evolução da doença.
46
à força da recomendação (Anexo 1). Na ausência de evidência direta, redigiram-se recomendações que refletissem o consenso unânime da comissão de especialistas.
e polifagia (aumento da sensação de fome). O DM não tratado pode causar muitas complicações macro e microvasculares, como a RD e o EMD.2
As diretrizes ressaltam os pontos-chave dos dados de duas maneiras. 1. Os pontos “para considerar” são extrapolaçõeschave dos dados e da prática clínica diária considerados importantes, mas para os quais a evidência publicada não é o suficientemente sólida. Por esse motivo, não receberam um valor baseado na evidência. 2. As “recomendações de consenso” são afirmações baseadas em evidência relativas ao manejo dos pacientes e contam com o respaldo da bibliografia citada. Realidade atual do diabetes mellitus
O emblemático estudo de controle e complicações do diabetes DCCT3 (Diabetes Control and Complications Trial) e sua continuação, o estudo de epidemiologia das intervenções e complicações do diabetes EDIC4 (Epidemiology of Diabetes Interventions and Complications), estabeleceram que o controle glicêmico intensivo reduz as complicações macro e microvasculares da doença em pacientes com DM tipo 1, inclusive o risco de apresentar retinopatias progressivas. Além disso, em ambos os estudos, as vantagens do tratamento intensivo foram mantidas durante um longo período.5-8
O diabetes mellitus (DM) compreende um grupo de doenças metabólicas nas quais o pâncreas não produz suficiente insulina ou suas células não respondem à insulina que produz.1 A doença caracteriza-se por sintomas de poliúria (micção frequente), polidipsia (aumento da sensação de sede)
No entanto, devemos estar cientes de que, além da insulina, a regulação da glicose abrange outros hormônios e diversos sistemas de órgãos.9 Além do mais, a insulina de reposição não imita completamente as ações da insulina secretada pelo pâncreas. Isso poderia ser uma possível explicação para
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
alguns dos eventos adversos observados no tratamento intensivo com insulina, como por exemplo, um aumento em três vezes da hipoglicemia grave, um aumento em três vezes das crises convulsivas e coma e um aumento no ganho de peso.10 No estudo prospectivo de diabetes do Reino Unido UKPDS (United Kingdom Prospective Diabetes Study) foi avaliada a função do controle glicêmico intensivo em mais de 5.000 pacientes com DM tipo 2.11 Em resumo, o estudo demonstrou que o controle intensivo da glicemia e da pressão arterial reduz o risco das complicações por diabetes. Os maiores efeitos de um rígido controle da glicose foram observados na redução das complicações microvasculares. Não houve diferenças importantes entre as diferentes farmacoterapias. Finalmente, no estudo de ação para controlar o risco cardiovascular no diabetes ACCORD (Action to Control Cardiovascular Risk in Diabetes) foi avaliado o impacto do controle intensivo da glicemia, dos lipídios e da pressão arterial em desfechos relacionados com Doença Cardivascular (DCV) em mais de 10.000 pacientes com diabetes tipo 2 e fatores de risco estabelecidos (ou seja, eventos cardiovasculares prévios, tabagismo, etc.).12,13 Embora o controle intensivo da glicemia e da dislipidemia tenha reduzido a taxa de evolução da RD, aumentou o risco de morte em pacientes com alto risco de ECV.13,14 Para considerar •
Os estudos não incluíram populações da América Latina, por isso os dados têm de ser extrapolados.
•
O tratamento glicêmico intensivo pode estar associado a um breve período de agravamento da doença ocular em alguns pacientes, principalmente durante os dois primeiros anos. A fim de controlar rapidamente a evolução da RD e as complicações que colocam em risco a visão, secundárias a esta evolução natural e inexplicável da doença, médicos oftalmologistas e especialistas em retina devem realizar acompanhamentos mais frequentes e potencialmente mais intensivos durante esse período inicial.
Recomendações de consenso 1. O controle glicêmico precoce e intensivo em pacientes diabéticos é necessário, porque reduz o risco de evolução da RD e do EMD em pacientes que não correm risco elevado de sofrer de ECV. [Nível 15,7,14] 2. Médicos oftalmologistas e especialistas em retina devem cuidar para que seus pacientes diabéticos também sejam tratados e recebam acompanhamento por especialistas em diabetes para que os desfechos terapêuticos sejam ideais. [Nível 3/Consenso] Epidemiologia do EMD e carga da doença Segundo dados publicados em 2013 pela Federação Internacional de Diabetes, aproximadamente 382 milhões de pessoas sofrem de DM em todo o mundo.15 E estima-se que até o ano de 2035 esse número aumente para 592 milhões. A RD e o EMD são complicações do DM altamente prevalentes e debilitantes relacionadas a problemas microvasculares do olho.16 Ainda que a RD esteja presente em 35% dos pacientes diabéticos, aproximadamente 8% desenvolvem uma forma proliferativa da doença.16 O EMD, definido como o espessamento da retina dentro de um diâmetro de dois discos da fóvea central, pode se manifestar em qualquer etapa da doença.17 Sua gravidade varia de leve e assintomática à perda de visão profunda.18 Estima-se que de 13% a 25% dos pacientes com DM desenvolvem EMD durante o transcurso de 10 anos19 e os que correm o maior risco são os pacientes com DM tipo 2 que usam insulina.20 A prevalência do EMD também varia com o estágio da RD; de 3%, naqueles com doença não proliferativa leve, a 71%, em pacientes com uma forma mais proliferativa.18 O EMD e o EMD clinicamente significativo (EMDCS) parecem ser mais prevalentes na populações da raça negra e de etnia hispana em relação aos chineses ou caucasianos.21-23 A prevalência do EMDCS na população com DM tipo 2 na América do Sul varia entre 3,4% e 5,5%.24 A alteração dos hábitos alimentares e o sedentarismo progressivo da população são dois dos fatores predisponentes.25 De
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
47
acordo com o estudo ocular realizado em latinos, Los Angeles Latino Eye Study, 37,4% dos diabéticos na América Latina sofrem de RD e 10,7% padecem EMD.26 Ambas as doenças têm consequências negativas na qualidade de vida e representam uma carga econômica significativa para o paciente, para os familiares, para a sociedade e para o sistema de saúde.27,28 Com relação à história natural, a doença ocular evolui do espessamento da retina ao comprometimento do centro e, finalmente, à deterioração da acuidade visual (AV). Se não for tratada, 15 letras do Estudo do Tratamento Precoce da Retinopatia Diabética (Early Treatment Diabetic Retinopathy Study - ETDRS) são perdidas no transcurso de três anos e o prognóstico geral é ruim.17 Este fato põe em destaque a necessidade de realizar a triagem, a detecção e o tratamento de forma precoce.29,30 O (Agoritmo 1) apresenta as recomendações relativas à triagem para casos de RD não proliferativa e proliferativa. Como a teleoftalmologia limita-se ao diagnóstico de doenças oculares, ela é vantajosa somente naquelas áreas em que possam ser oferecidos tratamentos subsequentes.31 Com o intuito de melhorar o tratamento da doença ocular diabética e reduzir seu impacto nos pacientes, na economia e nos sistemas de saúde, é necessário contar com programas de conscientização pública e estudos de epidemiologia.16,32 Mais pesquisas são necessárias para melhorar o entendimento do papel potencial que cumprem os fatores de risco e a predisposição genética a fim de moldar os programas de saúde pública.
•
A falta de conscientização sobre o DM e suas consequências constitui um problema de significância na América Latina. Cerca da metade da população de diabéticos na América Latina não tem conhecimento de que é portadora da doença e dão entrada no sistema de saúde quando notam alterações na sua visão.
•
Fatores genéticos e de estilo de vida contribuem para a prevalência crescente de DM, RE e EMD na América Latina.
•
Estudos epidemiológicos atuais carecem das definições adequadas relacionadas à etnia. A definição e a classificação dos pacientes segundo sua etnia são necessárias para avaliar a predisposição genética para RD e EMD.
•
A escassez de especialistas em retina é um problema sério em todos os países da América Latina.
Recomendações de consenso
Algoritmo II Tratamento da Retinopatia Proliferativa Em alguns casosb, é vantajoso tratar os pacientes antes do desenvolvimento de critérios de alto risco Estudo de retinopatia diabética Características de alto risco Presença de qualquer uma das seguintes situações: • Neovascularização • NVD • Gravidade da neovascularização o NVD > tamanho de ¼ área de disco o NVE > tamanho de 1/2 área de disco •Hemorragia pré-retiniana ou vítrea
b Pacientes que moram longe da clínica, evidência de doença de rápida evolução, cumprimento questionável do tratamento, pacientes com diabetes tipo 2 ou pacientes mais idosos.
Evidência de edema macular central
Manter-se afastado de qualquer área de tração durante a FPR SIM A FPR pode estar associada ao risco de fibrose. Deve-se ter precaução. c Conforme os critérios do ETDRS c FPR + Anti-VEGF
FPRc
Vasos em crescimento e/ou parecem ativos
Presença de hemorragia (visualmente significativa ou não resolvida)
Aumento de FPR
Anti-VEGF
RDP progressiva depois de FPR máxima
NAO
Vitrectomia
Hemorragia resolvida
SIM,
Aumento de FPR
NVR= neovascularização do disco; NVE = neovascularização em outro sítio; FPR = fotocoagulação panret´inica; VEGF = fator vascular de crescimento endotelial; ETDRS = early treatment diabetic retinopathy study; RDP= retinopatia diabética proliferativa
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
3. Todos os países ou regiões devem empenhar-se em coletar dados epidemiológicos para avaliar a prevalência de DM, RD e EMD. [Nível 3/Consenso] Os diferentes métodos de coleta de dados devem ser registrados e levados em consideração quando forem interpretados os desfechos dos estudos epidemiológicos. [Nível 3/Consenso] 4. Do ponto de vista do médico oftalmologista, o DM continua sendo uma doença mal definida. Portanto, os algoritmos para acompanhamento nos diversos estágios da doença precisam ser estabelecidos. [Nível 3/Consenso]
NAO
Realizar acompanhamento pós-FPR depois de 3 meses
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Para levar em consideração
5. Para obter êxito e melhorar os índices de saúde, os programas de conscientização pública e de triagem devem receber apoio por meio de infraestrutura adequada que garanta o acompanhamento e o tratamento daqueles que precisam. [Nível 3/Consenso] Fisiopatogenia do EMD O mecanismo exato por meio do qual a hiperglicemia crônica causa a RD e o EMD
não é completamente compreendido; mas, é muito provável que seja multifatorial. A rota comum inicia-se com a interrupção da barreira hematorretininana (BHR) interna, causando permeabilidade dos vasos e movimento de água.33,34 A ruptura da BHR interna é um processo complexo que envolve mudanças na zonula occludens (zônula oclusiva), perda de pericitos, perda de células endoteliais, leucostase dos vasos retinianos, super-regulação do transporte vesicular e tração vitreorretiniana. Observamse alterações estruturais e funcionais em neurônios e tecido glial em fases precoces da doença, muito antes de serem percebidas as alterações nos vasos.33 A hiperglicemia contínua afeta a vários fatores vasoativos, como o fator de crescimento endotelial vascular (vascular endothelial growth factor – VEGF), a proteína quinase C (PKC), a heparina, a angiotensina II e o fator derivado do epitélio pigmentado (pigment epithelium derived factor – FDEP).35,38 Isso causa o aumento da permeabilidade e vazamento da BHR.39 O VEGF, a citocina mais estudada das envolvidas na patogênese do EMD, é produzido por muitas células da retina.40-46 A hipóxia relacionada à vasoconstrição e vazamento capilar dá lugar ao aumento da expressão do VEGF e ao aumento da permeabilidade vascular.47,48 Foi proposto que algumas formas de PKC também desempenham um importante papel na permeabilidade dos vasos causada pelo VEGF.36 Desse modo, não é de surpreender que inibidores da PKC tenham reduzido significativamente o vazamento de fluoresceína causada pelo VEGF.36 A evidência clínica e anatômica também indica que as anomalias presentes na interface vitreorretiniana podem desempenhar um papel importante na patogênese do EMD.49 Por exemplo, a aderência do humor vítreo na mácula está relacionada a um aumento do edema macular. O acúmulo de produtos finais da glicação avançada (advanced glycation end-products - AGEs) no córtex vítreo causa o aumento de aderência do humor vítreo posterior à membrana limitante interna (MLI). Para levar em consideração • As interações e a função de várias citocinas na patogênese da DR e do
Tabela 1. Terminologia de TCO padronizada pelo DRCR.net
Termo
Definição
Espessura da retina
Valor em micras da distância entre as camadas de TCO que supostamente sejam o epitélio pigmentado retiniano e a membrana limitante interna
Espessura da retina
O valor calculado equivalente à espessura menos a média da população para a variável em consideração
Ponto central
A intersecção de seis varreduras radiais
Espessura do ponto central
A média dos valores de espessura das seis varreduras radiais no seu ponto de intersecção
Subcampo central
A área circular de 1 mm de diâmetro centrada ao redor do ponto central
Espessura média do subcampo central
O valor médio dos 128 valores de espessura obtidos no subcampo central
TCO = tomografia de coerência óptica; DRCR.net = Rede de pesquisa clínica sobre retinopatia diabética. Browning DJ et al. Ophthalmology 2008;115(8):1366-1371.
EMD ainda precisam ser mais bem compreendidas. O fato de que em 10% dos pacientes dos estudos RIDE e RISE50 a doença tivesse evoluído aos 24 meses, a despeito da total eliminação do VEGF, indica o envolvimento de outras vias. •
Diferenças na patogênese da doença podem impactar as decisões terapêuticas.
Recomendação de consenso 6. Ainda que muitos fatores participem da patogênese da DR e do EMD, a função do VEGF na patogênese do EMD é a mais compreendida. Assim sendo, a transdução de sinais relacionada ao VEGF é atualmente a única via de tratamento aprovada e recomendada. [Nível 150-57] Modalidades de exames por imagem no tratamento do EMD: Aplicação dos últimos avanços Na prática médica diária Importância da angiografia normal e panorâmica no diagnóstico do EMD Por mais de 50 anos, a angiografia com fluoresceína (AF) desempenhou um papel fundamental no tratamento do EMD.58,59 Por permitir uma melhor compreensão da fisiopatogênes da doença, os padrões de hiperfluorescência e hipofluorescência são guias úteis nas decisões terapêuticas.59 Assim sendo, mesmo com os recentes avanços em outras técnicas de exames por imagem, entre as quais a tomografia de coerência óptica (TCO), a AF continua sendo fundamental na avaliação dos desfechos terapêuticos.60 Uma das limitações da técnica convencional da AF é sua incapacidade de captar uma única imagem de todo o fundo de olho.61 Como as câmeras padrões de AF costumam captar uma imagem a PADRÕES DE BOAS PRÁTICAS EM RE E EMD
49
Tabela 2. Escala de gravidade da retinopatia diabética (RD
Nível de gravidade proposto da doença
Achados observáveis na oftalmoscopia com dilatação
Sem retinopatia aparente
Sem anomalias
RD não proliferativa leve
Somente microaneurismas
RD não proliferativa moderada
Mais que simples microaneurismas, mas menos que uma retinopatia diabética não proliferativa grave
RD não proliferativa grave
Qualquer uma das seguintes: • vinte hemorragias intrarretinianas em cada um dos quatro quadrantes; • rosário venoso definido em dois ou mais quadrantes; •
RD proliferativa
anomalias microvasculares intrarretinianas proeminentes em ≥1 quadrantes sem sinais de retinopatia proliferativa.
Um ou mais dos seguintes: neovascularização, hemorragia vítrea/ pré-retiniana
Wilkinson CP et al. Ophthalmology 2003;110(9):1677-1682.
30° ou 50°, o Estudo de Retinopatia Diabética (Diabetic Retinopathy Study) desenvolveu um protocolo que consiste em sete imagens padrões a 30°.62 A largura deste grupo combinado de imagens é aproximadamente de 75°. No entanto, costuma haver isquemia diabética e ausência de perfusão capilar na porção média da periferia63 que podem passar despercebidas com a angiografia convencional. As técnicas de imagem de ângulo amplo com fluoresceína captam imagens do fundo de olho de até 200° de amplitude, permitindo a detecção de anomalias periféricas, como ausência de perfusão periférica ou vazamento nos vasos periféricos.59,61 Isso poderia permitir uma abordagem com laser mais específica e gradual, que minimize os efeitos adversos provocados pelo laser como a perda de campo visual e o edema de mácula.59 São necessários mais estudos sobre a significância dos sinais periféricos retinianos detectados pela angiografia panorâmica. Importância da TCO no diagnóstico do EMD A TCO é um método diagnóstico não-invasivo e sem contato que utiliza reflexos da luz infravermelha para produzir imagens de cortes transversais confiáveis, reproduzíveis e objetivas das estruturas retinianas e da interface vitreorretiniana.64-67 Desde a sua introdução no início da década de 1990, a TCO contribuiu com novas informações sobre alterações morfológicas da retina em pacientes com DM e se transformou na ferramenta diagnóstica e prognóstica mais importante no tratamento da RD e do EMD.68-75 No EMD, é
50
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
utilizada na avaliação da espessura de retina, do edema macular cistóide, dos exsudados intrarretinianos e do líquido subrretiniano.71,72 Por meio de uma revisão bibliográfica sistemática em que a TCO foi comparada com exames diagnósticos convencionais (fotografia estereoscópica de fundo de olho ou biomicroscopia) chegou-se à conclusão de que a TCO apresenta bom desempenho no diagnóstico do EMD.74 A TCO também é importante no monitoramento da resposta ao tratamento e foi aceita unanimemente pela rede de pesquisa clínica sobre retinopatia diabética (Diabetic Retinopathy Clinical Research Network - DRCR.net) nos seus estudos que envolvem diagnóstico, tratamento e acompanhamento de pacientes com EMD.68,75,76 O rápido desenvolvimento e melhoria da instrumentação da TCO contribuíram ainda mais para o amplo uso da tecnologia.68,77 Sistemas de TCO mais antigos empregam a detecção no domínio do tempo (DT), na qual a posição do espelho de referência e o tempo de atraso são varridos mecanicamente para medir sinais de maneira sequencial desde diferentes profundidades e produzir varreduras axiais.73,76 Mais recentemente, encontra-se disponível no mercado a detecção no domínio espectral ou de Fourier. A TCO no domínio espectral (TCO-DE) utiliza um interferômetro com um espectrômetro de alta velocidade para medir simultaneamente sinais de luz durante todos os tempos de atraso e, dessa forma, proporcionar imagens axiais de maior resolução.78-80 A TCO-DE apresenta várias vantagens com relação à TCO-DT, entre as quais melhor resolução, melhor velocidade de aquisição da imagem e redução de artefatos de movimento.68,81 A maioria dos estudos em curso, no entanto, ainda é obrigada a coletar dados por meio de TCO-DT e, atualmente, não foi publicado nenhum estudo clínico grande, prospectivo e multicêntrico que utilizasse a TCO-DE. Além disso, a DCRC.net conta com termos padronizados para a tecnologia de TCO-DT Stratus (Tabela 1).82 Padrões comuns de TCO no EMD: 1) espessura difusa da retina (presente em quase todos os olhos com EMD), 2) edema macular cistóide (identificado em 44% a 47% dos olhos com EMD) e 3) descolamento seroso da retina (presente em 3% a 31% dos
olhos com EMD).83 Além disso, o limiar clínico para alteração na espessura por meio da TCO é geralmente >11%, porque foi observado que a variabilidade das medições da espessura retiniana pela TCO é <11% nos diabéticos, independentemente da presença ou não de EMD.84,85 A TCO com profundidade de imagem aprimorada (TCO-PIA) é utilizada para a avaliação da coróide.86 Isso é importante porque a espessura da coroide está intimamente relacionada com o estágio da RD e com o grau ou tipo de EMD. O espessamento progressivo da camada coróide, que ocorre com a evolução da RD ou o desenvolvimento do EMD, pode refletir a evolução simultânea da coroidopatia diabética. Dessa forma, a TCO-PIA é uma tecnologia não-invasiva que possibilita a avaliação precisa das alterações vasculares da coroide em pacientes diabéticos. Para levar em consideração •
A relação entre a não-perfusão periférica e o EMD ainda não foi estabelecida.
•
A AF panorâmica é uma estratégia de imagem emergente. Oferece mais informações se comparada com a técnica convencional; mas, é um processo lento e dispendioso.
•
A AF panorâmica poderia melhorar a eficácia do tratamento com laser por ter a capacidade de detectar com mais precisão as áreas periféricas que precisam de tratamento.
•
•
Os ensaios clínicos que conduziram à aprovação dos tratamentos atuais do EMD aplicaram a TCO-DT como uma das medidas de desfecho. Por conseguinte, na atualidade, a TCO-DT deveria ser suficiente para poder tomar decisões relativas ao tratamento do EMD. A TCO-DT, contudo, depende da habilidade do operador (a maioria dos estudos clínicos que empregaram a TCO-DT utilizaram centros de leitura), e com a TCO-DE há menos erros associados ao operador.81 Por oferecer mais detalhes quanto à localização e subtipo das lesões, a TCO-DE pode ser utilizada como ferramenta prognóstica.81 Existem
indícios de que uma coróide mais delgada poderia constituir-se em um marcador de maior risco de evolução da doença. •
A TCO-PIA é uma ferramenta promissora, mas ainda se encontra em fase exploratória. Existem indícios que corroboram a relação da espessura da coróide com a evolução do EMD.
Recomendações de consenso 7. A AF continua sendo uma ferramenta importante para avaliar o vazamento e orientar nas decisões terapêuticas em pacientes com EMD. [Nível 158,60,62] 8. Embora útil para a avaliação de pacientes que não respondem ao tratamento, a AF de campo amplo não é necessária para o tratamento adequado de pacientes com EMD. [Nível 3/Consenso] 9. Visto que a TCO pode medir objetivamente a espessura da retina, ela é considerada uma ferramenta importante e deve ser utilizada no diagnóstico e tratamento de EMD. [Nível 174,76,82] O ideal seria utilizar a TCO-DE porque oferece maior compreensão da morfologia da retina. [Nível 3/Consenso] Classificação da RD e do EMD A classificação da evolução natural da RD é fundamental para a tomada de decisões clínicas e para a comunicação entre colegas e entre especialidades médicas. A classificação original da RD foi descrita no Simpósio de Airlie House, em 1968.87 Desde então, vários sistemas modificados de classificação foram desenvolvidos e integrados nas diretrizes publicadas.88-90 Esses sistemas de classificação, utilizados para classificar fotografias de fundo de olho, são baseados na compreensão da evolução natural da RD obtida do ETDRS. A classificação do ETDRS é considerada o padrão-ouro para uso em estudos clínicos e epidemiológicos.89 No entanto, a aplicabilidade do sistema de pontuação do ETDRS na prática clínica diária é limitada, devido aos seus vários níveis de gravidade, normas Tabela 3. Escala de gravidade do edema macular diabético (EMD)
Nível de gravidade proposto da doença
Achados observáveis na oftalmoscopia com dilatação*
EMD aparentemente Sem espessura retiniana aparente ausente ou exsudados duros no polo posterior EMD leve
Alguma espessura retiniana ou exsudados duros no polo posterior, mas distantes do centro da mácula
EMD moderado
Espessura retiniana ou exsudados duros próximos ao centro da mácula, mas sem acometimento do centro
EMD grave
Espessura retiniana ou exsudados duros com acometimento do centro da mácula
* Exsudatos duros são um sinal de edema macular atual ou anterior. O EMD é definido como a espessura da retina que requer uma avaliação tridimensional. Esta avaliação é melhor com exame do olho dilatado mediante biomicroscopia com lâmpada de fenda e/ou fotografia estereoscópica de fundo de olho. Usado e adaptado com autorização de Wilkinson CP, et al. Ophthalmology 2003;110(9):1677-1682.
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
51
Para levar em consideração
Algoritmo III Tratamento de edema macular subclínico
•
Com relação ao tratamento do EMD, é importante avaliar se o edema é difuso ou focal, central ou periférico, e avaliar a proliferação e a tração. Para futuras classificações do EMD, essas características da doença devem ser levadas em conta.
•
As classificações do EMD também devem incluir um prognóstico e o risco de evolução, nos quais os médicos responsáveis pelo tratamento poderão basear-se para programar acompanhamentos adequados e oportunos dos pacientes.
Paciente diabético com visão funcional relativamente boa (20/25) e evidência de TCO de edema macular subclínico (isto é, um cisto)
Paciente refere redução de visão e pergunta sobre opções terapêuticas SIM
NAO Considerar a abordagem “observar e esperar” com avaliação depois de 2 meses.d
Considerar iniciar anti-VEGFd
É preciso aplicar a opinião clínica. A angiografia de fluorescência pode ajudar a definir as razões da redução da visão. Atualmente, o ranibizumabe é o único tratamento anti-VEGF provado para o EMD.
d
Se os cistos não forem resolvidos, considerar iniciar anti-VEGF apesar da ausência de sintomas, visto que os cistos podem danificar a retina a longo prazo.
de pontuação complicadas e a necessidade de correlação com imagens retinianas padrão.90 Esses requisitos são muitas vezes desnecessários na pratica diária e na atenção ao paciente. A escala internacional da gravidade clínica da retinopatia diabética (International Clinical Diabetic Retinopathy Disease Severity Scale), publicada em 2003, foi adotada por diversas diretrizes clínicas internacionais.90 Esta nova classificação internacional incorpora a evidência da evolução da doença a partir do ETDRS e, de acordo com as alterações na retina, estratifica a RD em cinco níveis de gravidade. Entre elas: 1) sem RD aparente; 2) RD não-proliferativa leve; 3) RD não-proliferativa moderada; 4) RD não-proliferativa grave e 5) RD proliferativa (Tabela 2). A escala internacional de gravidade clínica do edema macular diabético (International Clinical Diabetic Macular Edema Disease Severity Scale) também é fácil de usar. O primeiro passo é avaliar a presença ou ausência de EMD. Se o EMD estiver presente, poderá ser categorizado como leve, moderado ou grave (Tabela 3).90 Esses sistemas internacionais de classificação foram aprovados pela maioria das autoridades internacionais, inclusive a Organização Mundial de Saúde, como sistemas padrão para orientar a prática baseada na evidência. Ainda que essas classificações não tenham substituído o ETDRS, têm sido guias muito úteis na triagem de populações e para facilitar a execução oportuna do tratamento.
52
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
Recomendação de consenso 10. As classificações internacionais são mais aplicáveis à prática clínica diária, especialmente no tratamento da RD, do que as classificações do ETDRS. Por conseguinte, elas devem ser utilizadas até que as classificações com novos parâmetros obtidas mediante novas técnicas de imagem diagnóstica estejam disponíveis. [Nível 3/Consenso] Modalidades de tratamento não-farmacológico Fotocoagulação a laser: potencialidades e limitações
História da fotocoagulação a laser O conhecimento do efeito da fotocoagulação nos olhos remonta ao ano 400 a.C., quando o filósofo grego Sócrates notou que olhar diretamente para um eclipse queimava a retina.91 Inspirado pelos efeitos que a observação sem proteção do eclipse solar de 1945 causou na mácula de um estudante de medicina, o oftalmologista alemão Gerard Meyer-Schwickerath converteu-se no pioneiro da coagulação da retina por meio da luz.92 Os primeiros fotocoaguladores de arco de xenônio produziram luz composta de vários comprimentos de onda nos espectros de luz visível e infravermelha.93 Esses instrumentos careciam de precisão, precisavam de uma longa exposição, causavam dor e provocavam muitas complicações. Sua aplicação resultou em queimaduras de toda a espessura da retina ao invés de queimaduras específicas de tecidos.94 O primeiro aparelho de laser foi o laser de rubi, inventado por Maiman em 1960.91 Era mais compacto e confiável que seus precursores e resultou eficaz no controle da RD proliferativa (RDP) em alguns estudos clínicos. A introdução do laser de argônio, em 1968, levou ao uso generalizado da fotocoagulação oftálmica com laser.95 O comprimento de onda ideal empregado para a fotocoagulação da retina é caracterizado pela boa penetração através da absorção média e máxima no tecido-alvo.91,96 O laser de argônio azul esverdeado (70% azul 488 nm, 30% verde 514,5 nm) foi o laser oftálmico predominante durante muitos anos. No entanto, devido a diversas desvantagens, foi substituído posteriormente por laser verde e amarelo.91,97,98
Evidência clínica chave para RD e EMD O estudo de retinopatia diabética (Diabetic Retinopathy Study – DRS),99 marco neste campo de especialização e conduzido em meados de 1970, demonstrou uma redução de 50% no risco de perda de visão grave em olhos com RDP ou RD não-proliferativa grave
tratada com fotocoagulação panretiniana (FPR) em relação aos olhos não tratados. A FPR reduziu o risco de perda de visão grave (definida como AV de 20/800 ou pior em duas consultas consecutivas a cada quatro meses), causada por complicações da RDP, de 14,0% a 6,2%, durante um período de dois anos.99,100 O ETDRS foi o primeiro estudo randomizado e controlado a examinar a fotocoagulação a laser no tratamento do EMD. No estudo foi observada uma redução considerável no risco de perda visual moderada (~3 linhas no ETDRS) em pacientes com EMD clinicamente significativo tratados com fotocoagulação focal.17,101 Por meio da análise do subgrupo com visão pior que 20/40 durante a avaliação inicial, foi demonstrado que 40% dos pacientes melhoraram em ≥6 letras depois de três anos.102 A eficácia da fotocoagulação a laser focal/ grade foi confirmada posteriormente no estudo DRCR.net.103 Durante um período de dois anos, o laser foi mais eficaz que a triancinolona intravítrea (1 mg ou 4 mg) para a maioria dos pacientes com EMD; a variação média no escore de letras da AV a partir da avaliação inicial foi de +1 ± 17 no grupo com laser, -2 ± 18 no grupo com 1 mg de triancinolona e -3 ± 22 no grupo com 4 mg de triancinolona; P=0,02 para laser vs. 1 mg triancinolona; P=0.002 para laser vs. 4 mg de triancinolona). Os resultados da TCO costumam ser equivalentes aos da AV. Os resultados deste estudo estabeleceram a fotocoagulação focal/grade como referência para comparação com outros tratamentos em estudos clínicos de EMD.103 No entanto, a fotocoagulação também está associada a efeitos adversos importantes. Para ser eficaz, o protocolo de fotocoagulação do ETDRS precisa que, em alguns casos, as queimaduras sejam localizadas próximas ao centro da mácula. Com o tempo, essas queimaduras podem se transformar em áreas de atrofia progressiva.104 A FPR também pode causar distúrbios visuais relacionados à perda de função do tecido retiniano queimado, bem como a defeitos do campo visual periférico, redução da visão noturna, redução da visão de cores e menor sensibilidade ao contraste.105 Além disso, pode contribuir ao desenvolvimento ou à evolução do EMD, hemorragia vítrea e descolamento de retina por tração.106,107
Tabela 4. Estudos randomizados e controlados que avaliaram a eficácia do ranibizumabe no EMD
Estudo
Grupos de estudo e resultados visuais
N
Desfecho
Variação média na AVMC •
Ranibizumabe 0,5 mg: +7,2 letras (P=0,01 vs. somente laser)
•
Laser focal/grade: -0,4 letras
READ-2
•
Ranibizumabe 0,5 mg + laser focal/grade: +3,8 letras
(Fase 2)
Ganho médio na AVMC
126 51
101
RESOLVE52 (Fase 2)
•
Ranibizumabe 0,5 mg: +7,7 letras
•
Laser focal/grade: +5,1 letras
•
Ranibizumabe 0,5 mg + laser focal/grade: +6,8 letras
6 meses
24 meses
Variação na AVMC desde o início 151
•
Ranibizumabe (0,3 e 0,5 mg)*: +10,3 letras (P<0,0001)
•
Tratamento simulado (laser): -1,4 letras
12 meses
Variação média na AVMC RESTORE53 345 (Fase 3)
•
Ranibizumabe 0,5 mg: +6,8 letras (P<0,0001 vs. somente laser)
•
Laser focal/grade: +0,9 letras
•
Ranibizumabe 0,5 mg + laser focal/grade: +6,4 letras (P=0,0004 vs. somente laser)
12 meses
Variação média na AV DRCR.net
•
Ranibizumabe 0,5 mg + laser imediato: +9 letras (P<0,001 vs. tratamento simulado)
•
Ranibizumabe 0,5 mg + laser diferido: +9 letras (P<0,001 vs. tratamento simulado)
•
Triancinolona 4 mg + laser imediato: +4 letras
•
Tratamento simulado + laser imediato: +3 letras
54
(Fase 3)
854
12 meses
Variação média na AV • DRCR.net55
361
Ranibizumabe 0,5 mg + laser diferido: +9.7 letras (P=0,02)
3 anos
•
Ranibizumabe 0,5 mg + laser imediato: +6,8 letras Ganho ≥15 letras RISE50
377
•
Ranibizumabe 0,3 mg: 44,8% (P<0,0001 vs. tratamento simulado)
•
Ranibizumabe 0,5 mg: 39,2% (P<0,001 vs. tratamento simulado)
3 anos
• Intervención simulada: 18,1 % Ganho ≥15 letras RIDE50
382
•
Ranibizumabe 0,3 mg: 33,6% (P<0,0001 vs. tratamento simulado)
•
Ranibizumabe 0,5 mg: 45,7% (P<0,0001 vs. tratamento simulado)
•
Tratamento simulado: 12,3%
3 anos
* Dados combinados AVMC = Acuidade visual melhor corrigida
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
53
Algoritmo IV Tratamento do edema macular clinicamente significativo sem tração vitreomacular
1.Tratamento do edema macular clinicamente significativo sem tração vitreomacular 2.Exsudatos duros a 500 μm do centro da fóvea, ou dentro desse valor, associados à espessura retiniana 3.Espessura retiniana em uma área de tamanho de 1 disco, dentro do diâmetro de 1 disco do centro da fóvea
Fácica
Com espessura macular central
Pseudofácica
Considerar angiografia de fluorescência Para avaliar a perfusão e ajudar a definir o vazamento como focal ou difuso Edema difuso
Considerar anti-VEGF
Edema focal
Considerar laser focal Efeitos a longo prazo do laser (isto é, cicatrizes) precisam ser levados em consideração
Considerar esteroides intravítreos caso o resultado com antiVEGF não seja desejável e o paciente apresente baixo risco de sofrer de glaucoma
3 a 4 injeções mensais anti-VEGF Avaliar presença de líquido na TCO depois de 3 meses e fazer angiografia depois de 6 meses SIM
SEM líquido + melhora da visão
Líquido intrarretiniano leve na TCO + visão estável
Continuar o tratamento sempre que existir melhora na TCO e a visão seja estável
Considerar monitoramento mensal + prn
Considerar monitoramento e tratamento mensal se não houver melhora no líquido
Quando não exista mais melhora
Se houver reaparecimento significativo de líquido, considerar repetir o tratamento É preciso aplicar a decisão clínica profissional.
Realizar a angiografia e considerar o seguinte:
1. Encerrar o monitoramento (se a melhora for satisfatória)
2. Esteroides intravítreos (especialmente se outros tratamentos não estiverem dando resultado)
3. Vitrectomia e peeling de membrana se houver tração macular
É preciso aplicar a decisão clínica profissional.
Para tentar reduzir esses efeitos adversos, muitos especialistas em retina utilizam atualmente uma técnica modificada do ETDRS (mETDRS).108,109 O mETDRS aplica queimaduras mais leves e menos intensas que aquelas especificadas originalmente no protocolo do ETDRS.109 No entanto, devemos levar em conta que nunca foi realizado um estudo direto para comparar o ETDRS com o mETDRS. Uma abordagem alternativa (grade macular leve [GML]) que envolve a aplicação de queimaduras leves e aplicadas espaçadamente na mácula, evitando a região foveal, foi analisada em relação ao mETDRS.109 Aos 12 meses após o tratamento, a técnica GML foi menos eficaz na redução do espessamento da retina medido por TCO que a abordagem atual do mETDRS de fotocoagulação a laser. Os algoritmos II, IV e V apresentam as recomendações relativas ao uso de laser no tratamento da RD e do EMD. O laser de varredura padrão (patterned scanning laser – PASCAL) e o laser com diodo de micropulso sublimiar são as duas últimas inovações desenvolvidas para minimizar a formação de tecido
54
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
cicatricial. Até agora, essas novas abordagens parecem ser eficazes, mas são necessárias experiências a longo prazo para definir suas funções exatas no tratamento do EMD. O fotocoagulador PASCAL (532 nm), introduzido em 2005, aplica rapidamente queimaduras em uma sequência predeterminada, dispostas em um padrão de vários pontos.110 A duração dos pulsos é reduzida de 10 a 30 mseg. De acordo com uma série de casos retrospectivos, observacionais, de 313 pacientes tratados entre 2006 e 2008, o laser de varredura padrão é comparável aos protocolos de laser convencionais utilizados para o tratamento de distúrbios retinianos vasculares.111 A estimulação fototérmica pode ser obtida por meio de laser de micropulso ou PASCAL e é projetada para atingir o epitélio pigmentado da retina com energia subletal e minimizar concomitantemente os efeitos térmicos negativos na retina. Foi demonstrado que o laser de diodos com micropulsos é tão eficaz quanto a fotocoagulação padrão com laser de argônio para reduzir o EMD, além de permitir a possibilidade de aumentar a frequência de administração.112 Essa nova tecnologia foi avaliada em diversos estudos clínicos113-115 e séries de casos.116-118 Em 2009, Figueira et al.113 comparam a eficácia e os efeitos adversos da fotocoagulação com laser verde convencional e com laser de diodo com micropulsos sublimiares no edema macular clinicamente significativo. Não houve diferenças estatisticamente significativas na AV melhor corrigida (AVMC), sensibilidade ao contraste e espessura retiniana entre as duas modalidades de laser aos 0, 4 e 12 meses. As cicatrizes produzidas pelo laser foram muito menos visíveis com o laser de diodo com micropulsos sublimiar em relação ao laser verde convencional. Em outro estudo clínico prospectivo, randomizado, controlado, com mascaramento duplo, a técnica de laser de diodo com 810 nm de micropulsos sublimiares aplicado em uma configuração de alta densidade foi superior à fotocoagulação padrão de mETDRS durante ao menos um ano de acompanhamento.25 Além disso, houve significativamente mais olhos que recuperaram um grau de visão considerável e menos os olhos que a perderam. Deve-se levar em conta também que o protocolo-padrão para a titulação e a seleção de energia para
estas novas abordagens de fotocoagulação ainda não foi desenvolvido. Para levar em consideração •
A regressão da neovascularização após a fotocoagulação leva tempo (de dois a três meses). Durante esse tempo, os médicos podem considerar um tratamento anti-VEGF.
•
A função visual e o campo visual devem ser levados em conta quando a doença ocular diabética e a resposta ao tratamento forem avaliadas.
•
O tratamento com laser é de difícil administração já que requer o uso de uma grade e de cálculos para aplicar o número adequado de queimaduras; principalmente quando forem utilizadas modalidades de baixa intensidade. Todos esses fatores que devem ser considerados no uso da fotocoagulação no tratamento da RD e do EMD na prática clínica originam variações significativas nos desfechos visuais.
•
É provável que, no futuro, o tratamento da RD e do EMD compreenda uma combinação de fotocoagulação e terapia anti-VEGF.
Recomendações de consenso 11. A FPR continua sendo o padrão-ouro para a prevenção da proliferação na RD de alto risco, (Algoritmo II). [Nível 117.101-103] 12. A evidência atual indica que, para o tratamento do EMD, o laser não é superior à terapia anti- VEGF. Os algoritmos IV e V apresentam as recomendações para o uso do laser no tratamento do EMD. [Nível 3/Consenso] Importância da vitrectomia no tratamento do EMD As principais indicações para a vitrectomia compreendem a tração da hialóide posterior e EMD difuso que não responde a tratamentos tradicionais com laser ou abordagens farmacológicas, sozinhos ou combinados.119-122 O algoritmo VII apresenta a recomendação para o uso de vitrectomia no tratamento do EMD.
Lewis et al.123 propuseram em 1992 que a vitrectomia poderia melhorar a função visual em olhos com tração da hialoide posterior. Hipoteticamente, nesses casos, a vitrectomia alivia a tração sobre a mácula gerada pelo humor vítreo, diminuindo consequentemente o edema. Em dois estudos realizados em inícios do ano 2000, foi demonstrado que a vitrectomia com peeling da membrana epirretiniana (MER) reduz o edema e melhora a AV.124,125 Além disso, o resultado do procedimento não dependeu da presença ou ausência de descolamento de vítreo posterior e MER.124 No entanto, os pesquisadores observaram que a redução da espessura da retina no período pós-operatório não foi concluída até quatro meses após o procedimento. Além disso, como a vitrectomia poderia estar associada a complicações graves, os autores sugeriram exames pré e pósoperatórios cuidadosos. Em um estudo mais recente realizado em 87 pacientes em nome da DCRC. net, a vitrectomia produziu resultados contraditórios.118 Embora houvesse uma redução de 50% na espessura da retina em 68% dos pacientes, e 38% dos pacientes apresentassem uma melhora de ≥10 letras na AVMC, a AV diminuiu em ≤10 letras em 22% dos pacientes. Com base nesses resultados, os autores estimaram que entre 28% e 49% dos olhos com EMD e tração vitreomacular terão algum grau de melhora visual; enquanto que de 13% a 31% sofrerão de uma redução na visão.119 Os resultados de diversos estudos que avaliaram o efeito da vitrectomia com MLI demonstraram que a vitrectomia com Algoritmo V
Tratamento do edema macular clinicamente significativo sem tração vitreomacular Sem evidência de espessura macular central
Laser focal ou anti-VEGF
Reavaliação clínica +/- TCO aos 3 meses pós-tratamento
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
55
Modalidades de tratamento farmacológico
Algoritmo VI
Tratamento do Edema Macular Clinicamente Significativo com Tração Vitreomacular Com evidência de espessura vitreomacular por tração Pode-se considerar anti-VEGF
Caso haja tração na TCO, considerar vitrectomia Caso a tração for persistente ou grave, considerar cirurgia de vitrectomia peeling reduz a espessura da retina, mas não melhora significativamente a AV.126-128 Em um estudo retrospectivo recente com 32 olhos foi proposto que os focos hiperrefletivos pré-operatórios nas camadas retinianas externas detectados por TCO-DE poderiam predizer a lesão fotorreceptora e um pior prognóstico após a vitrectomia para o EMD.129 A avaliação da membrana limitante externa (MLE) antes da operação prediz com maior precisão a melhora da visão do que a junção fotorreceptora dos segmentos interno e externo (SI/SE) e a espessura macular central nos olhos com EMD. Por conseguinte, a avaliação da MLE poderia permitir aos médicos a avaliarem os resultados de uma vitrectomia. Em resumo, o estágio do EMD parece ser de especial importância para os resultados da vitrectomia. A evidência clínica não é sólida; mas, apresenta benefícios em casos selecionados. Para levar em consideração •
É difícil determinar se o edema é a causa da exsudação ou a consequência de uma reação inflamatória.
Recomendações de consenso 13. A vitrectomia deve ser considerada na presença de tração macular (Algoritmo VII). [Nível 2119-122] 14. Também poderia ser considerada a possibilidade de uma vitrectomia se o edema não responder à farmacoterapia (Algoritmo VII). [Nível 3/Consenso]
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PADRÕES DE BOAS PRÁTICAS EM RE E EMD
Terapias anti-VEGF
Função do ranibizumabe no tratamento do EMD O ranibizumabe é um fragmento de anticorpo humanizado dirigido a todas as isoformas do VEGF-A, fabricado especificamente para uso intravítreo.130 A eficácia e a segurança do ranibizumabe para o tratamento do EMD foram avaliadas em diversos estudos clínicos randomizados e controlados de fase II (READ-251 e RESOLVE52) e de fase III (RESTORE,53 RISE e RIDE50, e DRCR.net54,55) (Tabela 4). Em todos os estudos, o ranibizumabe foi superior ao grupo controle (laser, tratamento simulado [sham] ou esteróides) quanto à melhora dos desfechos visuais e anatômicos (TCO). Também é importante observar que o ranibizumabe foi eficaz na melhora da visão independentemente do controle glicêmico e dos níveis da hemoglobina A1c. Deve-se ter em mente, no entanto, que esses estudos diferem quanto aos cronogramas terapêuticos. Os pacientes incluídos nos estudos RESTORE e DRCR.net receberam uma dose de carga de três injeções mensais, seguida de controle mensal e tratamento segundo a necessidade (pro re nata [prn]), conforme o protocolo do estudo. Os pacientes que participaram dos estudos RISE e RIDE receberam injeções contínuas de ranibizumabe durante três anos. A evidência mais recente dos estudos RISE, RIDE e DRCR.net também indica que pacientes com EMD tratados com ranibizumabe apresentam um risco significativamente menor de desenvolver RDP do que aqueles que receberam o tratamento simulado.56,57 O tratamento com ranibizumabe também parece impedir a evolução das retinopatias existentes, conseguir a regressão de dois passos nos estágios da RD em um terço dos pacientes e melhorar os resultados visuais e anatômicos nesses pacientes.
Função do bevacizumabe no tratamento do EMD A evidência do bevacizumabe intravítreo (1,25 mg ou 2,5 mg) para o tratamento do EMD provém de estudos
clínicos pequenos e estudos de casos retrospectivos.131-135 Isso traz consigo limitações de significância que precisam ser levadas em consideração durante a interpretação dos dados. O estudo com bevacizumabe ou tratamento com laser (Bevacizumab or Laser Therapy – BOLT) é o maior ensaio disponível no momento e oferece o maior grau de evidência sobre o bevacizumabe no tratamento do EMD.136,137 BOLT foi um estudo de fase II, unicêntrico, de dois anos de duração, no qual foram comparados os efeitos do tratamento intravítreo com bevacizumabe com os do tratamento com laser administrados repetidamente em 80 pacientes com EMD persistente que causou danos visuais moderados.136 Resultados após dois anos demonstraram um ganho médio de +8,6 letras em pacientes tratados com bevacizumabe em relação a -0,5 letras com laser.137 A proporção de pacientes que ganhou ≥ 10 letras foi significativamente maior no grupo com bevacizumabe do que com laser (49% versus 7%, P = 0,001). Além disso, nenhum paciente tratado com bevacizumabe perdeu ≥ 15 letras, enquanto que 14% dos pacientes no grupo com laser tiveram uma perda ≥ 15 letras (P = 0,03). Em um estudo randomizado, prospectivo, de pequeno porte, realizado recentemente em 63 olhos com EMD com comprometimento central, foi comparado o bevacizumabe intravítreo (1,5 mg ) com ranibizumabe (0,5 mg).138 Embora ao ano de haver começado o estudo a eficácia de ambos agentes com relação à AV e à espessura de subcampo central (ESC) tivesse sido semelhante, o tratamento com ranibizumabe acelerou a redução da ESC e a recuperação da AVMC. O número médio de injeções foi maior no grupo com bevacizumabe.
Função emergente do aflibercept no tratamento do EMD O aflibercept (VEGF Trap-Eye) é uma proteína de fusão dirigida ao VEGF-A, ao VEGF-B e ao fator de crescimento placentário (FCP).139,140 No estudo Da Vinci de fase II, o aflibercept (0,5 mg ou 2 mg a cada quatro semanas e 2 mg a cada oito semanas) foi superior ao laser quanto à melhora da visão
e à redução da espessura da retina central (ERC) às semanas 24 e 52.141,142 À semana 52, maiores porcentagens de pacientes tratados com aflibercept demonstraram melhora no escore da gravidade da retinopatia diabética (Diabetic Retinopathy Severity Score – DRSS), quando comparados ao grupo com laser (31% a 64% para os grupos com aflibercept versus 12% para o grupo com laser).142 Além disso, olhos tratados com aflibercept apresentaram menor probabilidade de piora do DRSS em relação aos olhos tratados com laser. Isso indica que a atividade biológica do aflibercept trata não apenas o EMD, mas também pode diminuir a gravidade da RD, mudando, dessa forma, a história natural da doença. Os dois ensaios de fase III – VIVID (realizados nos EUA) e VISTA (realizados na Europa, Japão e Austrália) – confirmaram a superioridade do aflibercept em relação ao laser.143 Nesses estudos, foram testadas duas doses de aflibercept: 2 mg a cada quatro semanas (c/4 sem.) ou a cada oito semanas (c/8 sem.). A dose c/8 sem. demonstrou eficácia semelhante à dose c/4 sem. A média de melhora da AVMC variou de 10,5 a 12,5 letras. No entanto, o padrão de “sobe-e-desce” da ERC, semelhante àquele observado com o mesmo esquema posológico em casos de degeneração macular relacionada à idade (DMRI),144 indica que a dose c/8 sem. poderia ser sub-ótima para alguns pacientes. Além do mais, o número de tratamentos no estudo Da Vinci durante a fase prn foi semelhante ao registrado com ranibizumabe nos estudos RESTORE53 e DRCR.net,54,55 indicando que o aflibercept não conta com a vantagem posológica. Também é importante ter em mente que, semelhante ao bevacizumabe, o aflibercept é um anticorpo completo e que a porção Fc poderia aumentar sua exposição sistêmica. Em geral, o tratamento com aflibercept foi bem tolerado nos estudos Da Vinci, VIVID e VISTA. Não houve diferença nos eventos adversos sistêmicos graves, inclusive eventos cardiovasculares, cerebrovasculares e tromboembólicos arteriais vasculares periféricos de acordo com os critérios do grupo Antiplatelet Trialists’ Collaboration.145,146 Algoritmos III a VI ilustram o uso recomendado da terapia anti-VEGF, especialmente o ranibizumabe, no tratamento do EMD. PADRÕES DE BOAS PRÁTICAS EM RE E EMD
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Para levar em consideração •
Sinais de edema macular na TCO devem ser levados em consideração ao decidir se o tratamento será aplicado ou reaplicado.
•
O cronograma mensal fixo utilizado nos estudos RISE e RIDE produz os melhores resultados. No entanto, esse cronograma está associado a uma carga considerável tanto para pacientes com EMD quanto para os profissionais médicos responsáveis pelo tratamento.
•
O uso concomitante de laser pode reduzir a frequência das injeções antiVEGF, sem melhora nos resultados visuais. No entanto, ainda faltam evidências sobre o momento adequado para a aplicação de laser em relação à injeção anti-VEGF. Nos estudos clínicos, o laser foi aplicado três meses após o início do tratamento com ranibizumabe. Inovações recentes em técnicas com laser podem continuar a contribuir para a melhoria da eficácia e segurança, reduzindo ao mesmo tempo a carga terapêutica.
•
Ao selecionar o tratamento para o EMD, os médicos devem levar em consideração as indicações aprovadas em seus respectivos países.
•
Dados do aflibercept confirmam ainda mais a eficácia de ter como alvo a rota do FCVE no tratamento do EMD. São necessários dados de longo prazo de estudos de fase III para poder extrair conclusões adicionais.
Recomendações de consenso 15. Os dados disponíveis estabeleceram o ranibizumabe, com ou sem laser, como o padrão-ouro para o tratamento do EMD. O ganho médio esperado na visão baseado na evidência disponível é entre oito e 12 letras. [Nível 151-55] Os dados de bevacizumabe respaldam a evidência de que a terapia anti-VEGF é eficaz no tratamento do EMD, mas há menos evidência que respalde sua recomendação. O estudo BOLT é o maior ensaio clínico randomizado com bevacizumabe para o tratamento do EMD realizado até o momento. [Nível 2136,137] 58
PADRÕES DE BOAS PRÁTICAS EM RE E EMD
Clínicos devem estar cientes de que o bevacizumabe não está aprovado para administração via intravítrea e devem assumir a responsabilidade quando for usado em indicações não-aprovadas. No entanto, o risco de não tratar é maior do que o risco de usar o fármaco para indicações não aprovadas. [Nível 3/Consenso] 16. Pacientes com EMD devem receber injeções mensais de ranibizumabe por, ao menos, três a seis meses consecutivos (dose de carga), até que o paciente seja considerado estável. A fase de carga deve ser seguida de consultas mensais de avaliação (visão, TCO). [Nível 1124,125,127,128] 17. Os critérios de repetição do tratamento devem ser baseados nas características individuais do paciente e em sua resposta ao tratamento. [Nível 3/Consenso] 18. O laser poderá ser aplicado a qualquer momento após o começo do uso de ranibizumabe. [Nível 3/Consenso] Corticosteroides para o tratamento do EMD Por causa das suas propriedades anti-inflamatórias e, até certo ponto, antiangiogênicas e antipermeáveis, o esteroide sintético triancinolona é considerado uma ferramenta importante no tratamento do EMD.103,147 A primeira fórmula da triancinolona disponível comercialmente foi o Kenalog®. Seu primeiro uso na oftalmologia foi para a prevenção da vitreorretinopatia proliferativa após cirurgia de descolamento de retina.148,149 Também é utilizado, em indicação nãoaprovada, para o tratamento do EMD.150,151 No entanto, conservantes incluídos na preparação do Kenalog (ou seja, álcool benzílico) podem causar inflamação intraocular (~8% dos pacientes tratados).150,152-154 Por outro lado, a triancinolona micronizada (com cristais menores) sem conservantes (Triesence®, Trivaris®) parece causar menos danos à neurorretina em relação ao composto regular.155,156 A evidência clínica indicou melhoras marcantes na AV e redução da espessura da retina após uma única dose de triancinolona.147 Gillies et al.157 demonstraram também a eficácia da triancinolona no tratamento do EMD resistente ao laser. Depois de cinco anos, 42% dos casos apresentaram melhora
de cinco letras. Outro estudo confirmou que o uso da triancinolona antes do laser duplica a probabilidade de melhorar a visão em ≥10 letras.158 A incidência de hipertensão ocular (~25% de pacientes experimentam um aumento temporário da pressão intraocular) e catarata (com uma dose de 4 mg em 83% de pacientes em três anos) poderia ser um problema.
Algoritmo VII - Vitrectomia Vitrectomía
É importante levar em conta que o estudo DRCR.net estabeleceu a superioridade do laser sobre a triancinolona.103 No entanto, não foi observada diferença no ganho de visão em olhos pseudofácicos tratados com ranibizumabe ou triancinolona em uma sub-análise desse estudo.54 Recentemente, dois implantes de esteroides foram avaliados no tratamento do EMD.159,160 Ozurdex® é um implante biodegradável de dexametasona de administração lenta injetado no humor vítreo. Durante os primeiros nove meses após o procedimento, o Ozurdex demonstrou superioridade em relação ao tratamento simulado mais laser, mas não houve diferença significativa entre os grupos de tratamento ao ano de seu início.159 Além disso, foram necessários cinco procedimentos no transcurso de três anos para controlar o edema. Em um estudo de fase II que incluiu 55 olhos vitrectomizados, a redução na espessura macular central e a melhora na visão duraram seis meses.160 Isso indica que o Ozurdex poderia proporcionar uma margem de oportunidade para esses pacientes durante a qual a eficácia de outras modalidades terapêuticas poderia ser melhorada.
Hemorragia Hemorragia en humor vítreo que no desaparece
Desprendimientos por tracción
Hemorragia en humor vítreo que desaparece pero reaparece con frecuencia
Desprendimiento regmatógeno por tracción
Tener en cuenta inhibidores de VEGF antes de la operación para reducir la hemorragia (si no hay elementos de tracción; evitar si hubiera fibrosis o contracción significativas)
Desprendimiento macular por tracción
Se requiere del criterio clínico cuando se tiene en cuenta un anti-VEGF preoperatorio Tener en cuenta inhibidores de VEGF después de la operación para reducir la hemorragia y las complicaciones asociadas con la vitrectomía
Iluvien®, um implante de 25 mg que contém 190 µg de fluocinolona, foi aprovado recentemente na Europa após os resultados do estudo FAME.161 Em um cronograma de 12 meses de repetição do tratamento e a capacidade de usar laser por seis semanas após o implante e a cada três meses posteriormente, o Iluvien foi superior às injeções de tratamento simulado aos três anos. Para levar em consideração:
Diferenciação entre pacientes que respondem e que não respondem ao tratamento
•
Como os esteroides só têm efeitos antiangiogênicos secundários, eles tratam apenas uma parte da patologênese do EMD.
•
•
Os benefícios associados aos esteroides são atenuados pelas preocupações sobre problemas como a hipertensão ocular e a formação de cataratas.
A duração do edema pode ser usada como fator preditivo da resposta ao tratamento: quanto maior for a duração do edema, pior será o resultado.
•
Para a definição de pacientes que não respondem ao tratamento pode ser considerado o protocolo DCRC.net.
•
Para monitorar a resposta dos pacientes aos tratamentos, é preferível utilizar a tabela do ETDRS, ao invés da tabela de Snellen.
•
A necessidade de acompanhamento frequente após o implante de Ozurdex constitui uma carga significativa tanto para o médico quanto para o paciente. Além disso, os efeitos dos esteroides começam a desaparecer depois de dois meses. Por esse motivo, essa abordagem terapêutica está associada a “muito esforço e pouco ganho”.
Recomendações de consenso 19. Como não há continuidade da melhora inicial da visão e da redução do edema, os esteroides não devem ser utilizados como monoterapia; mas, sim em combinação com outras modalidades terapêuticas. [Nível 3/Consenso] 20. A rápida redução do edema alcançada com esteroides proporciona uma margem de oportunidade para o uso de outras abordagens terapêuticas como o laser ou a terapia anti-VEGF. [Nível 2160] 21. Os esteroides podem ser considerados para pacientes pseudofácicos (Algoritmo IV). [Nível 254]
Para levar em consideração:
Recomendação de consenso 22. Embora seja considerado que um paciente com clara melhora na visão e na anatomia responde ao tratamento, o paciente sem alteração na AV depois de três a seis meses de injeções anti-VEGF e sem alterações na TCO (espera-se uma melhora de ao menos 30 µm a 50 µm após uma segunda injeção) deve ser considerado como paciente que não responde ao PADRÕES DE BOAS PRÁTICAS EM RE E EMD
59
tratamento. Para esse paciente, deverá ser considerada uma modificação no tratamento. [Nível 3/Consenso] Segurança das farmacoterapias no tratamento do EMD Diferenças na estrutura molecular de três agentes anti-VEGF eficazes no tratamento do EMD são refletidas nas suas propriedades farmacológicas, as quais poderiam responder pelas diferenças nos seus perfis de segurança.162-166 O ranibizumabe, um fragmento de anticorpo de aproximadamente 48 dDa, foi projetado especificamente para uso intravítreo.130,167 O bevacizumabe e o aflibercept, por outro lado, são anticorpos completos inicialmente desenvolvidos para a administração intravenosa em pacientes oncológicos.168,169 Embora a eliminação sistêmica do ranibizumabe após o uso intravítreo seja de aproximadamente duas horas,167 a eliminação sistêmica de aflibercept e bevacizumabe é significativamente mais prolongada: quatro a cinco dias para aflibercept139,170 e cerca de 20 dias para bevacizumabe.169 O transporte através da barreira hematorretiniana desde o olho até a circulação sistêmica é atribuído ao fragmento Fc da molécula e seus receptores expressos em diversos tecidos oculares.171,172 A afinidade pelo VEGF também difere entre os tratamentos anti-VEGF intravítreos.173 O ranibizumabe tem uma alta afinidade pelo VEGF-A, e o aflibercept, pelo VEGF-A, VEGF-B e PGF.174,175 Ainda não se sabe ao certo qual o papel que o amplo espectro de afinidade do aflibercept possa cumprir fora do olho, especialmente visto que os dados mais recentes indicam um efeito neuroprotetor do VEGF-B.176 Como o VEGF desempenha um importante papel na angiogênese, reparação vascular e homeostasia, sua supressão sistêmica pode provocar efeitos deletérios potenciais em muitos sistemas de órgãos.177,178 Por exemplo, foi demonstrado que a supressão do anti-VEGF em pacientes com câncer traz consigo inúmeras consequências adversas, como problemas de cicatrização de feridas, hipertensão, trombose arterial, insuficiência cardíaca, proteinúria e efeitos renais adversos.178 Essa possibilidade de comprometer a segurança sistêmica é
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de especial importância ao selecionar o tratamento para pacientes diabéticos que já se encontram em alto risco de complicações cardiovasculares e renais. É importante observar que os estudos clínicos que avaliam os tratamentos antiVEGF para doenças oculares não foram impulsionados para comparar sua segurança sistêmica. Como o ranibizumabe foi desenvolvido e aprovado para uso intravítreo e para tratamento de doenças oculares, seu perfil de segurança foi comprovado e estabelecido com base em estudos clínicos de grande porte.179,180 Esses estudos conduziram, subsequentemente, à aprovação regulamentar do fármaco para várias doenças oculares, inclusive a DMRI e o EMD. Em estudos clínicos de grande porte, os eventos oculares foram semelhantes entre o tratamento simulado e o ranibizumabe. Por outro lado, o uso nãoaprovado e a reconstituição necessários para a preparação do bevacizumabe para uso intraocular estiveram associados a casos de endoftalmite bacteriana grave que culminaram em resultados visuais ruins.181,182 Por esse motivo, os médicos devem lembrar que o bevacizumabe não está aprovado para uso intraocular e, nesse sentido, precisa ser reconstituído por uma farmácia de manipulação. Os agregados de alto peso molecular também foram encontrados no bevacizumabe reembalado.183,184 Isso poderia causar a obstrução da saída do humor aquoso e a subsequente elevação da pressão intraocular e glaucoma.185,186 As taxas de eventos cardiovasculares observados nos estudos clínicos com ranibizumabe foram baixas e condizentes com as taxas observadas na população em geral.179 Por outro lado, os sinais de segurança de dois estudos clínicos de grande porte em pacientes portadores de DMRI indicam uma maior incidência de eventos adversos graves, especialmente complicações gastrointestinais com bevacizumabe em relação ao ranibizumabe.162,163 Isso é comparável com a faixa de advertência do bevacizumabe intravenoso que inclui o comprometimento da cicatrização de feridas e perfuração gastrointestinal.169 Uma advertência semelhante é incluída no rótulo de Zaltrap® (formulação intravenosa de aflibercept).186
Em resumo, embora os sinais de segurança dos estudos clínicos relativos à administração intravítrea de antiangiogênicos sejam poucos, os médicos responsáveis pelo tratamento devem levar em consideração o fato de que, na prática clínica, os pacientes diferem daqueles que participam em estudos clínicos. As co-morbidades podem contribuir ainda mais para a manifestação de eventos adversos indesejáveis. Com relação aos esteróides intraoculares, é fato estabelecido que seu uso conduz ao aumento da pressão intraocular, glaucoma e, possivelmente, catarata.157,158,187-189 O laser está associado a complicações de cicatrização.97,190-192 Para levar em consideração: •
O tratamento de pacientes diabéticos pode ser mais difícil que o daqueles com DMRI e oclusão de veias da retina devido à natureza sistêmica da doença e co-morbidades associadas.
Recomendações de consenso: 23. Dados de estudos clínicos de grande porte estabeleceram um perfil de segurança favorável para o ranibizumabe. Além disso, o perfil de segurança do ranibizumabe no EMD é consistente com aquele observado em pacientes com DMRI. [Nível 1179,180] No entanto, como faltam dados de segurança para outros antiangiogênicos (bevacizumabe e aflibercept), a farmacovigilância é necessária. Além do mais, os médicos devem lembrar que o bevacizumabe não é indicado para administração intravítrea. [Nível 3/Consenso] 24. Como os esteróides intravítreos podem produzir um aumento da pressão intraocular, glaucoma e catarata, é importante ter cuidado e realizar acompanhamentos frequentes do paciente [Nível 1157,158,187-189]. 25. Médicos devem ter em mente que o tratamento com laser pode gerar cicatrizes e complicações relacionadas. [Nível 197,190-192] 26. O estado de saúde geral dos pacientes diabéticos precisa ser levado em
consideração ao selecionar o tratamento do EMD. [Nível 3/Consenso] 27. Médicos devem empregar os mais elevados padrões de assepsia durante o procedimento de administração. [Nível 3/Consenso] Catarata e EMD Pacientes diabéticos são de duas a quatro vezes mais suscetíveis do que os não diabéticos a sofrerem de catarata.193 O risco é maior em pacientes com RD proliferativa, aqueles com mais de 40 anos de idade e pacientes dependentes de insulina.194 A relação entre a cirurgia de catarata e a história natural da RD não é bem clara. Também não se sabe bem ao certo até que ponto o tratamento da RD e do EMD realizado antes da cirurgia de catarata afeta seu resultado. Três situações importantes para levar em consideração: •
Pacientes que precisam de cirurgia de catarata, mas sem necessidade de retinopatia
•
Foi demonstrado que pacientes com retinopatia pré-existente correm maior risco de evolução da retinopatia, acometimento de edema macular e perda da visão em relação àqueles sem retinopatia pré-existente195
•
Pacientes que precisam tanto de cirurgia de catarata quanto de vitrectomia
•
Embora haja sido comprovado em diversos estudos que o prognóstico visual é semelhante quando ambos os procedimentos são realizados simultaneamente, do ponto de vista do paciente, é preferível realizar os procedimentos em sequência196,197
•
Pacientes com cristalino limpo que precisam de vitrectomia, mas não uma cirurgia de catarata
•
Em todos os casos, a avaliação préoperatória é essencial e deve incluir a avaliação da AV, exame de fundo de olho, TCO e ultrassonografia.
Embora as causas de edema macular pós-cirurgia de catarata não sejam completamente compreendidas, acreditase que citocinas inflamatórias, mediadores
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vasoativos e a tração da membrana hialoide desempenhem algum papel.198 Como o VEGF contribui para diversas alterações fenotípicas observadas no edema macular,199 em estudos recentes foi demonstrado que o uso de antiangiogênicos intravítreos combinados com facoemulsificação pode prevenir o desenvolvimento de EMD pós- operatório após a cirurgia de catarata.200-206 Para levar em consideração: •
Não está claro se o edema após a cirurgia de catarata em pacientes diabéticos é um EMD “verdadeiro” ou apenas um edema pós-operatório que pode ser tratado com colírio antiinflamatório não-esteróide .
•
A TCO pode ser útil para determinar se o edema se encontra na camada nuclear externa ou interna.
•
Como o EMD geralmente afeta a camada externa, ela pode ser utilizada como guia das opções terapêuticas.
•
O anti-VEGF pré-operatório poderia evitar o desenvolvimento de edema pósoperatório, mas a evidência não é sólida.
•
Os cistos grandes da retina devem ser tratados antes da cirurgia de catarata, porque podem sofrer ruptura durante o procedimento e danificar a retina.
Recomendações de consenso 28. O primeiro passo no tratamento do edema após cirurgia de catarata em pacientes diabéticos é a abordagem “observar e esperar” por um a dois
meses ou colírios anti-inflamatórios não-esteroides. Em caso de edema persistente, podem ser considerados os antiangiogênicos ou esteróides intravítreos. [Nível 3/Consenso] 29. O tratamento de EMD antes da cirurgia de catarata precisa ser bem documentado. [Nível 3/Consenso] 30. O edema de pacientes com EMD precisa estar controlado (tratado, estável e responsivo ao tratamento) antes da cirurgia de catarata. [Nível 3/Consenso] 31. Se, depois da cirurgia de catarata, houver formação de edema no olho contralateral, este deverá ser examinado e tratado de maneira independente. [Nível 3/Consenso] Tratamentos emergentes Como o VEGF cumpre uma importante função na patogênese da RD e do EMD, ainda continua a pesquisa dirigida à rota de transdução de sinais do VEGF (isto é, degradação do ácido ribonucleico [RNA] mensageiro do VEGF utilizando pequenos RNAs interferentes, bloqueio de receptores de VEGF, etc.).207 Além disso, estão sendo pesquisadas outras citocinas implicadas na patogênese da doença (por exemplo, o fator de necrose tumoral),208 além da proteína quinase C209 e o alvo de rapamicina em células de mamíferos210. Outras modalidades terapêuticas para os estágios iniciais do desenvolvimento clínico compreendem a terapia genética,211,212 a tecnologia nãocodificante, que emprega uma fibra de oligonucleotídeos que se liga a um RNA mensageiro específico, inibindo-o,213 a terapia com peptídeos ligantes de integrina214 e proteínas de repetição de anquirina projetadas.215 Além do mais, outras opções prontamente disponíveis não devem ser desconsideradas em casos difíceis, como abordagens cirúrgicas,216,217 novas modalidades com laser218 e implantes com esteroides.160 Para levar em consideração: Os antiangiogênicos estabeleceram um marco muito alto, dificultando a capacidade de novos tratamentos de atingir seus mesmos níveis de eficácia, segurança, praticidade de administração e custo.
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Defining the standard of care in DME* LUCENTIS® (ranibizumab) ABBREVIATED UK PRESCRIBING INFORMATION Please refer to the SmPC before prescribing LUCENTIS 10mg/ml solution for injection. Presentation: A glass single-use vial containing 0.23ml solution containing 2.3mg of ranibizumab (10mg/ml). Indications: The treatment in adults of neovascular (wet) age-related macular degeneration (AMD), the treatment of visual impairment due to diabetic macular oedema (DMO), the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Administration and Dosage: Single-use vial for intravitreal use only. LUCENTIS must be administered by a qualified ophthalmologist experienced in intravitreal injections under aseptic conditions. The recommended dose is 0.5 mg (0.05ml). For treatment of wet AMD: Treatment is given monthly and continued until maximum visual acuity is achieved i.e. The patient’s visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab. Thereafter patients should be monitored monthly for visual acuity. Treatment is resumed when monitoring indicates loss of visual acuity due to wet AMD. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month. For treatment of visual impairment due to either DMO or macular oedema secondary to RVO: Treatment is given monthly and continued until maximum visual acuity is achieved i.e. the patient’s visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment. If there is no improvement in visual acuity over the course of the first three injections, continued treatment is not recommended. Thereafter patients should be monitored monthly for visual acuity. Treatment is resumed when monitoring indicates loss of visual acuity due to DMO or to macular oedema secondary to RVO. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month. LUCENTIS and laser photocoagulation in DMO and in macular oedema secondary to BRVO: When given on the same day, LUCENTIS should be administered at least 30 minutes after laser photocoagulation. LUCENTIS can be administered in patients who have received previous laser photocoagulation. For treatment of visual impairment due to CNV secondary to PM: Treatment is initiated with a single injection. If monitoring reveals signs of disease activity, e.g. reduced visual acuity and/or signs of lesion activity, further treatment is recommended. Monitoring for disease activity may include clinical examination, optical coherence tomography (OCT) or fluorescein angiography (FA). While many patients may only need one or two injections during the first year, some patients may need more frequent treatment. Therefore, monitoring is recommended monthly for the first two months and at least every three months thereafter during the first year. After the first year, the frequency of monitoring should be determined by the treating physician. The interval between two doses should not be shorter than one month. LUCENTIS and Visudyne photodynamic therapy in CNV secondary to PM: There is no experience of concomitant administration of LUCENTIS and Visudyne. Before treatment, evaluate the patient’s medical history for hypersensitivity. The patient should also be instructed to self-administer antimicrobial drops, 4 times daily for 3
days before and following each injection. Children and adolescents: Not recommended for use in children and adolescents due to a lack of data. Elderly: No dose adjustment is required in the elderly. There is limited experience in patients older than 75 years with DMO Hepatic and renal impairment: Dose adjustment is not needed in these populations. Contraindications: Hypersensitivity to the active substance or excipients. Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. Special warnings and precautions for use: LUCENTIS is for intravitreal injection only. Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Monitor during week following injection for infections. Patients should be instructed to report symptoms suggestive of any of the above without delay. Transient increases in intraocular pressure (IOP) within 1 hour of injection and sustained IOP increases have been identified. Both IOP and perfusion of the optic nerve head should be monitored and managed appropriately. Concurrent use in both eyes has not been studied and could lead to an increased systemic exposure. There is a potential for immunogenicity with LUCENTIS which may be greater in subjects with DMO. Patients should report an increase in severity of intraocular inflammation. LUCENTIS should not be administered concurrently with other anti-VEGF agents (systemic or ocular). Withhold dose and do not resume treatment earlier than the next scheduled treatment in the event of the following: a decrease in best corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; an intraocular pressure of ≥30 mmHg; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or if the size of the haemorrhage is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days. Risk factors associated with the development of a retinal pigment epithelial (RPE) tear after anti-VEGF therapy for wet AMD include a large and/or high pigment epithelial retinal detachment. When initiating LUCENTIS therapy, caution should be used in patients with these risk factors for RPE tears. Discontinue treatment in cases of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. There is only limited experience in the treatment of subjects with DMO due to type I diabetes. LUCENTIS has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy, or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with LUCENTIS in diabetic patients with an HbA1c over 12% and uncontrolled hypertension. In PM patients there are no data on the use of LUCENTIS in patients with extrafoveal lesions and only limited data on its use in those who have had previous unsuccessful therapy with verteporfin photodynamic therapy. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. There are limited data on safety in the treatment of DMO, macular oedema due to RVO and CNV secondary to PM patients with prior history of stroke or transient ischaemic attacks. Caution should be exercised when treating such patients. There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic BRVO and CRVO. Treatment is not recommended in RVO patients presenting with clinical signs of irreversible ischaemic visual function loss. Interactions: No formal interaction studies
have been performed. In DMO and BRVO adjunctive use of laser therapy and LUCENTIS was not associated with any new ocular or non-ocular safety findings. Pregnancy and lactation: Women of childbearing potential should use effective contraception during treatment. No clinical data on exposed pregnancies are available. Ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving. Breast-feeding is not recommended during the use of LUCENTIS. Driving and using machines: The treatment procedure may induce temporary visual disturbances and patients who experience these signs must not drive or use machines until these disturbances subside. Undesirable effects: Most adverse events are related to the injection procedure. Serious adverse events reported include endophthalmitis, blindness, retinal detachment, retinal tear and iatrogenic traumatic cataract. The safety data below include adverse events experienced following the use of LUCENTIS in the entire clinical trial population. Those marked * were only seen in the DMO population. Very Common: Intraocular pressure increased, headache, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, arthralgia, nasopharyngitis. Common: Urinary tract infection*, anaemia, retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia, cough, nausea, allergic reactions, hypersensitivity, anxiety. Product-class-related adverse reactions: There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. A low incidence rate of arterial thromboembolic events was observed in the LUCENTIS clinical trials in patients with AMD, DMO, RVO and PM and there were no major differences between the groups treated with ranibizumab compared to control. Please refer to the SmPC for full listing of all undesirable effects.
For UK: Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis Pharmaceuticals UK Ltd on (01276) 698370 or medinfo.uk@novartis.com Legal category: POM, UK Basic NHS cost: £742.17. Marketing authorisation number: EU/1/06/374/001. Marketing authorisation holder: Novartis Europharm Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom. Full prescribing information, including SmPC, is available from: Novartis Pharmaceuticals, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR. Telephone: 01276 692255. Fax: 01276 692508. Prepared July 2013.
*Visual impairment due to diabetic macular edema
Lucentis Indications may vary from country to country. Physicians should refer to their National Prescribing Information. Novartis Pharma AG CH-4002 Basel, Switzerland
©2014 Novartis Pharma AG September 2014 146882
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This special supplement has been peer reviewed by the Editorial Scientific Board of Vision Pan-America, The Pan-American Journal of Ophthalmology and published according to the guidelines provided by the U.S. National Library of Medicine on Conflict of Interest Disclosure and Journal Supplements http://www.nlm.nih.gov/pubs/factsheets/supplements.html Individual Disclosure of Conflict of Interest ICMJE Form for Disclosure of Potential Conflicts of Interest 1. Dr. P. Schlottmann reports personal fees and non-financial support from Novartis; personal fees and non-financial support from Bayer; personal fees and non-financial support from Allergan, outside the submitted work; 2. Dr. C. Acosta reports lecture fees and non-financial support from Novartis and Bayer. 3. Dr. L. Bicas reports lecture fees and non-financial support from Bayer. 4. Dr. D. Lavinsky reports financial support from Novartis and a grant from TMLS 5. Drs. AA Alexandrini, FM Damico, JA Roca, J Bafalluy, ME Farah and RA Jorge have nothing to disclose. 6. Dr. G. Dib reports PERSONAL FEES. 7. Dr. RA Cano reports non-financial support from NOVARTIS, outside the submitted work.
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BEST PRACTICE STANDARDS IN DIABETIC RETINOPATHY AND DME