Vitrase Effective for Vitreous Hemorrhage Management
Statistically significant outcomes were seen as early as the month of treatment.
Vitreous hemorrhage, a major vision-threatening problem, occurs in seven per 100,000 people each year in Europe. If the statistics are similar in the United States, then about 20,000 new cases of dense spontaneous hemorrhage occur annually.
The most common cause of vitreous hemorrhage is complication from proliferative diabetic retinopathy (PDR). There are other causes such as branch or central retinal vein occlusion, posterior vitreous detachment with or without retinal tear or detachment and ocular trauma.
It is thought that the pathologic foundation of vitreous hemorrhage in retinal vascular disease is the development of retinal ischemia that induces retinal neovascularization. The new abnormal blood vessels that develop grow into the vitreous cavity, using the vitreous as a scaffold. The vitreous traction on these new vessels results in vitreous hemorrhage.
Patients with type 1 diabetes have a higher risk of developing PDR than those with type 2 diabetes. These patients therefore have more frequent and more severe ocular complications. Early visualization of the retina to identify and treat the underlying causative disorder is critical to maximize the return of visual function.
My colleagues and I recently reported our study in the American Journal of Ophthalmology. We pooled results from two multinational, randomized, double-masked, controlled trials of intravitreous injection of ovine hyaluronidase. Patients included in the phase 3 trials had vitreous hemorrhage ≥1 month that was severe at entry and BCVA worse than 20/200.
See Underlying Pathology
To determine efficacy, clearance of the hemorrhage had to be sufficient enough to see the underlying pathology and completion of the treatment when indicated. This was measured at months 1, 2 and 3. The key secondary endpoints included ≥3-line improvement in BCVA, hemorrhage density reduction and therapeutic utility assessment.
The patients were randomized to receive 55 IU or 75 IU of ovine hyaluronidase or saline.
The intention-to-treat population was 1,125 patients; at baseline, 76.3% had diabetes, 90.4% were unable to read any letters on the eye chart, and the mean hemorrhage duration was 120 days (Table 1).
We found that statistical significance was reached in the patients assigned the 55-IU dose by months 1 and 2 for the primary efficacy endpoint using an adjusted P-value. By treatment months 1, 2 and 3, 13.2%, 25.5% and 32.9% of the patients in the 55-IU dose group reached primary efficacy compared with 55%, 16.2% and 25.6% of patients who were assigned saline (P<.001, P=.002, P=.025, respectively).
The treatment effect was confirmed by the key secondary endpoints at both doses and all time points (P≤.01).
Pooled Safety Data
In the pooled safety data, published in the same journal, no serious safety issues were reported after the single injection. Retinal detachment incidence was not statistically different between treatment and placebo groups, with iritis manifesting as an acute self-limited inflammation as the most common adverse event. This occurred in a dose-response fashion, but was not noted to result in a serious adverse event in any treated eye.2
These studies were the first of their kind to evaluate the efficacy of an enzymatic agent for the management of vitreous hemorrhage. The management options currently available are observations and pars plana vitrectomy. Enzymatic vitreolysis offers several potential advantages over the current standard practice, including the ability to diagnose and treat the eye earlier, at a lower cost and with greater patient availability.
Although the primary endpoint was to be achieved by month 3, it was seen as early as month 1, the earliest time point at which efficacy was assessed, and through month 2 in a statistically significant proportion of patients treated with a single injection of 55 IU.
Key Secondary Endpoints
We found that the relative difference in the primary efficacy of 55 IU ovine hyaluronidase compared with saline was greater by month 1. Also, the relative difference by month 2 was greater than by month 3. The three key secondary endpoints are corroborative of this finding: The endpoints were reached with statistical significance by month 1 and persisted through month 3 (Table 2).
Although the initial management of vitreous hemorrhage is often conservative, there is evidence that early clearance of vitreous hemorrhage is associated with improved long-term preservations of useful vision and an improved quality of life. For some patients, a nonsurgical option may restore vision at an earlier time point and positively impact their quality of life.
Baruch D. Kuppermann, MD, PhD, is in the department of ophthalmology at the University of California, Irvine. Dr. Kuppermann is a member of the Retina Today editorial board. He disclosed that he is a consultant for Ista Pharmaceuticals. He may be reached at firstname.lastname@example.org.
1. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthal. 2005;140:573-584.
2. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Safety results of two phase 3 trials of an inravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthal. 2005;140(4):585-597.