Bevacizumab and Long Acting Gas in Diabetic Vitrectomy
Condition: Proliferative Diabetic Retinopathy
MeSH terms: Retinal Diseases; Diabetic Retinopathy
Study type: Interventional
Phase: Phase 3

Summary: 
      Persistent or recurrent vitreous hemorrhage after vitrectomy for diabetic retinopathy
      complications is a common occurrence with an incidence of 12% to 63%. This complication may
      prolong vitreous clear-up and delay visual rehabilitation significantly, and sometimes
      requires additional procedures or surgery.

      The causes of bleeding are diverse. Evidence suggests fibrovascular proliferation from the
      sclerotomy sites or from the vitreous base may be an important source of recurrent vitreous
      hemorrhage; other sources of bleeding include iatrogenic intraoperative injury of retinal
      vessels, and incomplete removal of fibrovascular tissues.

      We have reported on the possible benefit of peripheral retinal cryotherapy and cryotherapy
      treatment of sclerotomy sites to prevent delayed-onset recurrent vitreous hemorrhage, and the
      possible benefit of intravitreal long-acting gas to reduce the occurrence of early
      postoperative recurrent vitreous hemorrhage, especially for cases with active fibrovascular
      proliferation. However, minor recurrent vitreous hemorrhage and prolonged reabsorption of
      lysed blood clots from surgical trauma remain important factors to cause media opacity long
      enough to prevent quick visual rehabilitation.

      Intravitreal bevacizumab has been noted to induce rapid regression of retinal and iris
      neovascularization in proliferative diabetic retinopathy. Further, presurgical administration
      of intravitreal bevacizumab may reduce intraoperative bleeding during membrane dissection in
      PDR with traction retinal detachment. We hypothesize that presurgical treatment of
      intravitreal bevacizumab may reduce intraoperative bleeding and the amount of residual blood
      clots, while intraoperative infusion of long-acting gas may facilitate post-operative
      recovery of surgically injured retinal vessels. These combined effects would thus enhance
      early clear-up of vitreous opacity from clot lysis and recurrent retinal bleeding. To
      investigate this hypothesis, a clinical prospective study was undertaken to evaluate the
      effects of bevacizumab pretreatment combined with intravitreal infusion of long-acting gas on
      the clearance speed and the recurrence rate of early postoperative vitreous hemorrhage in
      vitrectomy for active diabetic fibrovascular proliferation.
    

Detailed description: 
      From December 2006 to August 2007, consecutive patients undergoing primary pars plana
      vitrectomy for active proliferative diabetic retinopathy were recruited for the prospective
      study. Included cases should have active fibrovascular proliferation with vitreo-retinal
      adhesions in 3 or more sites but not extending beyond equator in more than one quadrant.
      Active fibrovascular proliferation is defined as visible new vessels within the proliferative
      membranes with any degree of fresh vitreous or preretinal hemorrhage. Exclusion criteria are:
      1. History of preoperative or postoperative anticoagulant therapy; 2. History of blood
      diseases associated with abnormal coagulation; 3. Severe proliferation with anticipation of
      silicone oil usage. Informed consent is obtained in every patient before surgery. The
      protocol was approved by the review board and research ethics committee of National Taiwan
      University Hospital.

      All cases in the study group are prospectively enrolled (group 1). Consecutive patients
      fulfilling the enrollment criteria receive intravitreal bevacizumab (1.25mg in 0.05ml)
      injection 7 to 9 days before surgery and intravitreal 10% C3F8 infusion at the end of
      surgery. The surgical outcomes are compared with a non-concurrent control group that received
      gas infusion only (group2). The control group is matched by baseline characteristics and the
      severity of diabetic proliferation with the study group. The comparisons between the two
      groups are possible because all the relevant parameters have been carefully documented in the
      control group. A single surgeon (CMY) performed all of the operations.

      Operative Technique For intravitreal bevacizumab injection, after topical anesthesia,
      patients were disinfected three times with povidone-iodine solution and draped. After eyelid
      speculum put in place, the eyes are further anesthetized with proparacaine -soaked cotton-tip
      applicators. Bevacizumab (1.25mg in 0.05ml) is drawn into a 1 ml syringe through a 27-gauged
      needle from a newly opened vial and injected through a 30-gauged needle into the vitreous
      cavity via temporal lower pars plana. Anterior chamber paracentesis is not performed.

      Standard 3-port pars plana vitrectomy as described previously is done in every case. In
      short, vitreoretinal traction, fibrovascular tissues, and opacified vitreous as well as blood
      clots adherent to the peripheral vitreous skirt are removed as completely and safely as
      possible. Hemostasis is obtained by raising the infusion bottle, mechanical compression using
      a soft-tipped cannula, endodiathermy, or a combination of the above techniques. Blood clots
      formed during tissue dissection are removed carefully except on the bleeding sites where they
      were trimmed to small islands. Panretinal photocoagulation in non-laser treated eyes or
      supplementary laser in previously laser-treated eyes extending beyond the level of the
      equator is performed. Further peripheral retinal cryotherapy (10 to 12 spots in one row) is
      done. 10% C3F8 intravitreal infusion is done in each case before wound closure. Finally,
      cryotherapy of the sclerotomy sites (1 spot, each 6 seconds, for 3 sclerotomy sites) is
      performed.

      After surgery, all patients are kept in a prone position overnight, and maintained a
      head-down position during waking hours. The patients are then allowed to lie on either side
      during sleep for 3 weeks thereafter. Ophthalmological examinations are performed in the first
      4 days after surgery, then weekly for 4 weeks, biweekly for 1 month, and then monthly for at
      least 6 months.

      The preoperative, intraoperative, and postoperative data are collected for each patient.
      These demographics and clinical findings included age, gender, study eye, types, duration and
      treatment regiment of diabetes mellitus, systemic diseases such as hypertension, renal
      insufficiency, intraoperative diagnosis, extent of vitreo-retinal adhesion, degree of
      intraoperative bleeding, duration of the surgery, and combined lens extraction. The extent of
      neovascularization, the severity of retinal traction, and the amount of fresh vitreous
      hemorrhage before and one week after bevacizumab injection were documented and, if possible,
      photographed. Data regarding the duration for vitreous clear-up; the time, duration,
      frequency and treatment of recurrent vitreous hemorrhage; and the duration of postoperative
      follow-up are also compiled. The extent of fibrovascular proliferation is graded as follows:
      grade 1, focal adhesions only; grade 2, broad adhesion ≥ one site(s) or vitreous-retinal
      adhesion at the disc, macula, and arcade; and grade3, vitreous-retinal attachment extending
      to the periphery. Intraoperative bleeding is classified into 3 grades : grade 1, minor
      bleeding that stopped either spontaneously or by transient bottle elevation; grade 2,
      moderate bleeding requiring endodiathermy or with formation of broad sheets of clots
      extending away from the bleeding site; grade 3, thick clot formation covering at least half
      of the posterior pole or interfering with the surgical plane.

      Results of ophthalmological examinations, including best corrected visual acuity, intraocular
      pressure, lens status, and intravitreal gas amount, are recorded. We define vitreous clear-up
      time (VCUT) as the interval between the end of the surgery and the time when visualization of
      retinal vessels regained below the gas bubble. VCUT equal to or more than 3 weeks is
      considered prolonged. We define recurrent vitreous hemorrhage as recurrent hemorrhage that
      obscured the retinal vessels (grade 2 or above in the Diabetic Retinopathy Vitrectomy
      Study14) for more than one week after VCUT. Both early (≤ 4 weeks) and late (> 4weeks)
      recurrent vitreous hemorrhage are recorded. The severity of vitreous hemorrhage was
      classified according to the scale defined in the Diabetic Retinopathy Vitrectomy Study, and
      is reconfirmed by another ophthalmologist for every patient. The VCUT, the rate and treatment
      of recurrent vitreous hemorrhage, and the change of best-corrected visual acuity were
      compared between groups 1 and 2. Visual acuity is graded into three levels: low (≤1 meter
      counting fingers), moderate (>1 meter counting fingers, but < 20/200), and good (≥ 20/200).

      Statistical Analysis To examine the differences among groups 1 and 2, discrete variables are
      performed statistical analysis with chi-squared test or Fisher's exact test. Continuous
      variables are presented as mean ± standard deviation and the Wilcoxon rank sum test was
      performed to make comparisons among groups 1 and 2. To further verify the effect of combined
      bevacizumab and gas treatment and to examine other possible factors affecting vitreous
      clear-up time, we would perform multivariate logistic regression analysis to determine the
      significance of the following factors: age, gender, duration of diabetes (< 10 years or ≥ 10
      years), treatment regiment of diabetes, prior pan-retinal photocoagulation, hypertension,
      renal insufficiency, extent of fibrovascular proliferation, duration of surgery, and
      intravitreal bevacizumab. All of the statistical analyses are performed using STATA 8.2
      software (StataCorp LP, College Station, Texas, USA). A P value < 0.05 was considered
      statistically significant.
    

Intervention name(s): Bevacizumab
Intervention type(s): Drug
Intervention description(s): Patients will receive intravitreal injection of 1.25 mg of bevacizumab (0.05 ml) 7 to 9 days before vitrectomy
Other intervention name(s): Avastin
Intervention MeSH terms: Bevacizumab
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: proliferative diabetic retinopathy; bevacizumab (Avastin); vitreous hemorrhage; long acting gas