Avastin® and Hypertension

I recently received this question:

My mother (age 76) recently had intraocular Avastin injection for wet ARMD in one eye About a week later, she had PDT followed by a steroid injection. The following day, she experienced severe HTN, requiring 2 days of hospitalization! I'm trying to find out how likely it was that the Avastin was the culprit.She did have pre-existing HTN, usually well-controlled except for during medical appts ("white coat HTN"). Sadly, no one at the ophth office took her BP before or after her injection!

The questions now are, "can she safely take Avastin in the future if her ARMD requires further treatment?" "Would switching to Lucentis be any safer, in respect to HTN?"She is mostly concerned about her eyesight. I'm more concerned about losing her to a stroke.

My response:

Hypertension is the main side-effect of Avastin® when it’s given for the treatment of colon cancer. For colon cancer the dose is 5milligrams (mg) per kilogram of weight. Someone who weighs 70 kilograms, (154 pounds), would get 350 mg intravenously. The intraocular dose for AMD is 1.25mg which is two hundred and eight times less than the intravenous dose. Doctors in Europe often inject 2.5 mg or twice the usual dose in the United States. Because the dose is so much less, we have thought it was very safe. Avastin has been given hundreds of thousands of times without reported side-effects but then doctors might not be anxious to publicize that they had a complication.

BUT- We know that Avastin injected into one eye can cause an effect in the other eye meaning that it must get into the bloodstream.1 We also know that Avastin and Lucentis can be detected in the bloodstream after either of them are injected into the eye. There have been recent concerns of an increased risk of stroke in a preliminary analysis of patients who received Lucentis®. (blog March 1, 2007)

Did the Avastin cause the high blood pressure in your mother? I don’t know but it is suspicious. We don’t know what her blood pressure was before the injection since it was never measured. Maybe it was already high and the Avastin tipped it over the edge. We also don’t know if the right amount of Avastin was injected into the eye. Could the pharmacy have diluted it incorrectly? It’s unlikely that the doctor injected too much because the increased volume would have caused elevated intraocular pressure and pain.

So what should you and she do now? I wouldn’t get another dose of Avastin. Lucentis may be a better option since its systemic half-life is much shorter. Of course Lucentis is smaller so more may get out of the eye in the first place and Lucentis binds VEGF more tightly than Avastin which may increase its systemic risk. Frankly I’m not too thrilled about Lucentis either.

I’m hoping that your mother doesn’t need any more treatment. She has received triple therapy with the Avastin, PDT, and steroid. Often only one round of this triple therapy is enough to cause resolution of the new blood vessels. If the vessels leak again, PDT with steroids alone may be a good option. PDT with steroids doesn’t have quite as good visual results as Avastin or Lucentis but they’re close. If your mother has already lost vision, the final results may not be different with PDT and steroids alone compared to combining them with Avastin or Lucentis. Plus she also has the other eye. My mentor, Dr. Robert C. Watzke, once said to me, “There are things worse than blindness.” He meant that I should weigh the risk of an operation to the chance of its success. I might tell your mother that, “There are things worse than losing maybe one more line of vision with a safe treatment.”

References:

1. Avery RL, Pearlman J, Pieramici, DJ, Castellarin AA, et al.” Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.” Ophthalmology. 2006 Oct;113(10):1695.e1-15.

Comment from reader re: PDT and Avastin

I would like to share with you an email I have had from a Radiologist in Australia who has macular degeneration.

Your comments on recent blog about PDT and Avastin seem to be very much true in my experience.

My left eye was repeatedly treated with PDT and over period of about 18 months, my central vision was lost though the neovascularization stopped. When I developed macular degeneration in the right eye, I had one session of PDT together with intra ocular steroid. I had re bleeding in three months when I was first treated with Avastin (that was time when Avastin become available in Australia). In almost 15 months since then I had three more injections of Avastin (at time of repeated bleeding) and my vision is holding on and good enough to let me work as Radiologist (though I avoid doing interventional work and injections). As a patient, I will definitely like to be treated with Avastin (or Lucentis) as I found its result to be more satisfying personally.

related posting

Avastin or Lucentis in Pregnancy

We received another question late last week:

Hi. I have a retinal lesion in each eye. The right one is fine, has been stable since July 2004, when both lesions were found. The right lesion was stopped by laser. My left eye, the lesion spread into my macula...laser treatments did not work. Macugen then came out and I had over a year of treatment with Macugen in my left eye. I haven't had a shot since August 2006, my left retina lesion has remained under control since then. However, I now have some leaking and I need a shot in left eye. I am pregnant, and I am asking as to whether you have heard of any other woman being pregnant getting a shot of Lucentis? My Retinal specialist has not, nor my OB-GYN....Thanks for your time.

I have heard of one pregnant woman who had an injection of Avastin for a choroidal neovascular membrane. I believe she was in her second trimester at the time. Her eye did fine and she had a completely normal baby. Keep in mind this is anecdotal evidence and not a controlled clinical study. I don’t think anyone knows the answer as to whether either of these drugs is safe in pregnancy. Genentech [http://www.fda.gov/cder/foi/label/2006/125156lbl.pdf] states that Lucentis should be given in pregnancy only if clearly needed. Pharmaceutical companies are very leery of litigation, so I think they would not have stated this if they thought there was more than a miniscule chance that the injection would hurt the mother or child.

I would like to know how good your vision was in the left eye before this flare-up. If you had poor vision anyway, you could consider waiting. If you’ve noticed worsening vision, then I think you should be treated and that you and your baby will do fine. I would recommend Lucentis rather than Avastin because of its shorter systemic half-life.

Problems with PDT

I received this message a few weeks ago:

Hi Dr Folk, My mother just had a PDT (visudyne) treatment and her dark area of central vision just doubled after the PDT. Should she switch to Avastin® or proceed on the PDT therapy, the second of which is scheduled after 3 months.

My comment is that the results of the various Lucentis® trials show that it’s a better treatment than PDT or Macugen®. There have been no randomized trials on Avastin® but hundreds of thousands of injections of it have been given around the world for wet AMD. The consensus and articles on nonrandomized trials so far is that Avastin® has pretty results that are the same or close to that of Lucentis® which would also make it better than PDT. Therefore I’m not sure why your mother received PDT as first line therapy. .

PDT causes inflammation with increase fluid exudation beneath the retina and a stimulus for regrowth of revascularization. It can also cause closure of choroidal capillaries beneath the macula and bleeding beneath the retina. All of these affects can cause vision loss. I’m not sure why your mother lost vision.

The downside of Lucentis® and Avastin® is that they stop the abnormal vessels from growing and leaking but they often don’t cause them to close permanently. Therefore injections of either drug have to be given repeatedly. PDT can close vessels permanently but sometimes at a price of vision loss. Doctors are now trying to determine which combinations may be most effective. The most common combination that is used now is PDT using half the amount of laser dose followed the same day with an injection of Lucentis® of Avastin®. Dr. Augustin and colleagues in Karlsruhe, Germany, used a combination of PDT with Avastin® and intraocular Decadron®, (an anti-inflammatory steroid) and had good results (ref 1). They also did a partial vitrectomy which may or may not have been necessary. Therefore PDT is still used but almost always as part of a combination treatment.

I don’t know your mother’s case. Maybe she has a lot of vascular risk factors which could make Avastin® or Lucentis® a little risky. There is a concern that these drugs could increase the risk of thromboembolic events especially strokes but we don’t know this for sure yet. Given the poor response to PDT, I would recommend Avastin® or Lucentis® if the choroidal neovascular vessels are still leaking or active.

References:

1. Augustin, AJ, Puls, S, Offerman I, “Triple Therapy for Choroidal Neovascularization due to Age-Related Macular Degeneration. Vertportfrin PDT, Bevacizumab, and Dexamethasone. RETINA 27:133-140, 2007.

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