COMMENTARY

New Studies Refine Treatment Options in Cerebral Bleeding

Hans-Christoph Diener, MD, PhD

Disclosures

December 23, 2016

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Dear colleagues, I am Christoph Diener, a retired neurologist from the University of Essen in Germany. Today, I'd like to discuss with you three recent articles in the New England Journal of Medicine, two of which deal with cerebral bleeding and one with herpes zoster.

Let's start with the article on intracerebral hemorrhage.[1] The most important risk factor for this is high blood pressure, which we know usually increases dramatically immediately after intracerebral hemorrhage. This is the rationale for the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial, which assessed whether aggressive lowering of systolic blood pressure can improve outcomes.

The investigators randomized people who had an intracerebral hemorrhage and a mean systolic blood pressure of 200.6 mm Hg into two groups that were treated within 4.5 hours of symptom onset. The systolic blood pressure target was between 110 and 139 mm Hg in the intensive treatment group and between 140 and 179 mm Hg in the less aggressive, standard treatment group. The primary outcome was the poor outcome of death or disability (measured by a modified Rankin scale score of 4-6) at 90 days.

The trial was ended prematurely because of futility, as it turned out that poor outcomes were 38.7% in the aggressive treatment group and 37.7% in the standard treatment group—a statistically similar result.

This is the already the second trial that looked at whether aggressive lowering of blood pressure in patients with intracerebral hemorrhage has a benefit. The study that was done before[2] had a 6-hour time window, whereas this one had a 4.5-hour window. This basically means, unfortunately, that we can take our time to treat high blood pressure in this patient group.

The next paper deals with andexanet alfa.[3] We have now three anti-factor Xa drugs for the prevention of stroke in patients with atrial fibrillation: apixaban, edoxaban, and rivaroxaban. For dabigatran, we have an improved and tested reversal agent in idarucizumab. And andexanet alfa is a reversal agent for the anti-factor Xa inhibitors.

In this study, 67 patients who had major bleeding on either rivaroxaban or apixaban were treated with andexanet alfa. This drug is given as a bolus followed by a 2-hour infusion. The main study endpoint was changes in measures of anti-factor Xa activity.

It showed that within a very short time and across 2 hours, the reduction in the median activity of anti-factor Xa was approximately 90%, which is a very good result. Unfortunately, the anti-factor Xa activity increased again 4 hours after the end of the treatment. In terms of clinical outcome, the judgment was that 37 out of 47 patients had good hemostasis, which is a very positive result.

Andexanet alfa is not approved yet, but as soon as it is, it will hopefully be available in emergency department to treat patients who have severe bleeding with apixaban or with rivaroxaban. Unfortunately, the trial did not treat patients who needed an urgent surgery or procedure, such as tissue plasminogen activator, following ischemic stroke.

The third trial[4] is relevant for you if you are aged 50 years or older, as I am, or if you have family members who are. It is well known that herpes zoster, and in particular postherpetic neuralgia, is a problem that increases in prevalence with age, and becomes a real problem after the age of 70. Now there is a new vaccination to prevent herpes zoster. This was investigated in 13,900 patients 70 years of age or older, who were randomized either to the vaccine or placebo and followed for 3.7 years.

The incidence of herpes zoster was 23 in the vaccinated group and 223 in the placebo group, reflecting a risk reduction of more than 90%. In terms of postherpetic neuralgia, there were four cases in the vaccination group and 36 in the placebo group—again representing a 90% risk reduction.

This study was pooled with a second trial where patients were included who were 50 years or older. The pooled analysis showed exactly the same outcome: an approximately 90% reduction in the risk for herpes zoster infection and postherpetic neuralgia.

This is a very important message. I have encouraged all my relatives who are 50 years of age or older to get vaccinated, and I myself got vaccinated because I do not want to get postherpetic neuralgia.

Ladies and gentlemen, these are three important studies on intracerebral hemorrhage, bleeding complications on anti-factor Xa inhibitors, and preventing postherpetic neuralgia in elderly people.

I am Christoph Diener, recording from Bangkok, Thailand, where it is unfortunately nighttime, so I cannot show you the skyline. Thank you very much for listening and watching.

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