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Rethinking the timing of therapies for acute ischemic stroke

New breakthroughs are changing experts

March 2007
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Published in the March 2007 issue of Today’s Hospitalist 

As the physicians on the frontlines of acute ischemic stroke diagnosis and treatment, hospitalists need to be up-to-date about rules governing which vessel-opening and clot-busting therapies to employ and when.

That’s more important now than ever, according to stroke expert S. Andrew Josephson, MD, because the field has undergone such significant advances in the last few years. Many of those advances, Dr. Josephson told a group of hospitalists at the University of California, San Francisco’s annual meeting on managing hospitalized patients, revolve around how to understand and maximize the timeline surrounding acute stroke.

Dr. Josephson, an assistant clinical professor of neurology at UCSF, said that according to recent guidelines, patients are eligible for intravenous tPA if a stroke is less than three hours old. If the stroke happened fewer than six hours ago, many centers use intra-arterial tPA. And if patients present within eight hours of a stroke, mechanical embolectomy is possible.

“The time of onset of stroke is the last time the patient was seen normal.”

andrewjosephson~ S. Andrew Josephson, MD, UCSF 

This last development is particularly important because it “increases our window for doing something in patients who have a potentially devastating stroke involving a large vessel occlusion,” he said. “This is a real success story.”

A two-fold approach
A big part of that success story stems from the FDA’s decision in 2004 to approve a clot retriever known as the MERCI retriever. The device is revolutionary, Dr. Josephson said, because it can remove blood clots from the brain in patients experiencing an ischemic stroke.

But the good news in stroke care advances doesn’t stop there. Stroke experts are currently making progress on new procedures, including combining agents and techniques that can not only make tPA safer, but extend the window in which the drug can be given.

Dr. Josephson said that most of the new approaches being studied share two overarching goals, which experts believe must take place in tandem if more stroke patients are going to have a fighting chance of surviving the infarction: opening the vessel and protecting the ischemic tissue.

“Where are we going with acute stroke treatment?” Dr. Josephson asked. “It’s really two-fold.”

“No. 1 is to open the vessels up,” he said. “The second is to give patients neuroprotective agents that protect the neurons that have been starving for blood flow within the first hours of a stroke.”

The current thinking, Dr. Josephson added, is that both approaches have to occur in parallel.

Maximizing “drip and ship” therapy
A set of closely watched trials, known as the Interventional Management of Stroke (IMS) trials, are looking at ways to combine intravenous tPA with local techniques to open the occluded vessel. The goal is to produce a therapy that generalists can give in any hospital, with intra-arterial tPA or embolectomy devices that are now available mainly from specialists at tertiary institutions.

By giving partial doses of tPA, the thinking goes, physicians can buy patients more time to allow for transfer to a tertiary health care center that can provide angiography and direct intra-clot lysis or retrieval.

Dr. Josephson said that this “drip and ship” strategy is important because of the ongoing national shortage of stroke neurologists and neurointerventionalists.

“We know that not everyone in the country is going to be initially treated at an institution with a trained neurointerventionalist,” he explained. A therapy that can be administered by a non-neurologist may be one way to stabilize patients so they can be sent to a neurointerventionalist.

Extending the stroke timeline
When it comes to understanding the timeline of acute stroke, there have also been significant breakthroughs in imaging. Dr. Josephson said that trials currently underway are examining imaging protocols that could let clinicians make decisions about how to use tPA, based less on time and more on characteristics of the infarction itself.

“It doesn’t make any sense that all patients after three hours can’t get IV tPA,” Dr. Josephson explained. “Some patients perhaps should not get intravenous tPA at any time, while others may be able to safely get the drug after 10, 12 or even 24 hours. We hope to be able to prove this through imaging studies.”

The focus on neuroprotective agents that can reduce disability from an acute ischemic stroke also may help “extend the time window” for using tPA safely, Dr. Josephson said. A number of trials with different agents and techniques to protect tissue while opening vessels are underway.

Starting the treatment clock
All these developments shine a light on the role hospitalists play in these patients’ lives.

“You are the people who matter in terms of stroke,” Dr. Josephson told the group of hospitalists. “Very few stroke patients will see a neurologist, and an even smaller number will see someone like me who is trained in neurovascular neurology. You will need to think about these techniques any time you see a patient in the first eight hours after a stroke.”

Consequently, he said, a vital part of a hospitalist’s job when confronted with a patient having an acute ischemic stroke is to determine how far along in the timeline that patient is “and what therapies are still an option.

One common mistake, Dr. Josephson said, is to overestimate how much time remains in that treatment window. For instance, if a patient wakes up at 8 a.m. and finds his or her right side impaired, physicians shouldn’t start the clock at 8 a.m. to determine if the patient is still eligible for tPA.

Instead, he said, the key time to begin that count is when the patient was last seen to be normal “at 5 a.m., for instance, when the patient got up to use the bathroom, or at 10:30 p.m. the night before when the patient went to bed. “That’s the time the stroke started,” he said, for the purpose of determining what acute therapy to try.

“The time of onset of stroke is the last time the patient was seen normal,” Dr. Josephson said. “Determining this time of onset is the most important question to ask patients and their families who present with acute stroke.”

Deborah Gesensway is a freelance writer who reports on U.S. health care from Toronto, Canada.

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The acute stroke timeline: What therapies can you use?
Timeframe* Therapy
0-3 hours: Intravenous tPA
0-6 hours: Intra-arterial tPA (a non-FDA approved therapy)
0-8 hours: Mechanical embolectomy
More than 8 hours: Anticoagulants or antiplatelets
* time of onset, from the last time seen normal