Treating acute ischemic stroke

By Phyllis Maguire - February 2014

Published in the February 2014 issue of Today’s Hospitalist

MOST HOSPITALISTS KNOW that IV tPA is the go-to therapy for many patients with ischemic
stroke “as long as you can deliver that therapy within 4.5 hours of symptom onset. But an
analysis of data that appeared in the June 19, 2013, Journal of the American Medical Association
drove home just how important speed is when administering IV tPA.

“For every single 15-minute interval that the medicine was given earlier, there were significantly
lower rates of in-house mortality and of intracerebral hemorrhage, and higher rates of people
walking by themselves at discharge,” explained stroke expert S. Andrew Josephson, MD, who
discussed treating acute ischemic stroke at last fall’s management of the hospitalized patient
meeting at the University of California, San Francisco (UCSF). “Most hospitals have now turned to
focusing on what they can do to speed up their time when giving tPA.”

But another recent study debunked the use of mechanical embolectomy after patients receive IV
tPA. And the list of stroke patients for whom you should prescribe anticoagulants just keeps
getting shorter, said Dr. Josephson, who heads UCSF’s neurohospitalist program.

“If I’d given this talk 25 years ago, a good number of patients would get Coumadin to prevent a
second stroke,” he noted. “Now, if you remember that we use Coumadin only for patients with
atrial fibrillation, that’s fine. That’s 99% of the indication to use anticoagulants for secondary
stroke prevention.”
Endovascular therapy and IV tPA
As many as one-third of patients who receive IV tPA have better outcomes at 90 days, Dr.
Josephson pointed out.

“There is no change in mortality, so you’re not saving or harming lives,” he said. “What you are
doing is preventing the morbidity from neurologic deficits that we’re all so worried about.”

But a study published in the March 7, 2013, New England Journal of Medicine (NEJM) delivered
one of last year’s big stroke headlines: Researchers randomizing patients to IV tPA alone or to IV
tPA followed by endovascular therapy if the clot was still present “either intra-arterial tPA or
mechanical embolectomy “stopped the trial early.

“There was absolutely no benefit to the combined therapies, and there was no single subgroup
who got better,” said Dr. Josephson of the IMS-III trial results. “We don’t think this approach
works in most patients.”

Some physicians have pushed back against those results, pointing out that two new devices
approved last year “which Dr. Josephson called “stents on a stick” ” can open up blood vessels
almost 90% of the time, instead of the 60% possible with devices used when the trial took place.

“The question is: If you re-did this trial with the new devices, would patients fare better?” said Dr.
Josephson. “We don’t know, and I think the data suggest that we shouldn’t be using these devices
following IV tPA, except as part of a randomized trial to answer that question.”

An important exception, he noted, is patients with basilar artery thrombosis, who were not
included in large numbers in the trials. “There’s reason to believe the devices are particularly
effective in that location,” he said.

Of course, endovascular therapies do remain key options for stroke patients who miss the 4.5-
hour window for IV tPA or for whom the therapy is contraindicated. Mechanical embolectomy is
approved for up to eight hours after symptom onset.

Anticoagulants: few indications

But beyond eight hours, the only treatment options doctors have are anticoagulants and
antiplatelets “and the list of patients who should be anticoagulated keeps on shrinking.

A fib patients top that list, and Dr. Josephson usually starts stroke patients with new onset a fib
on warfarin the day they are admitted or the day after (without bridging heparin) unless they’ve
suffered a massive stroke. In patients with an extraordinarily large infarction, “I’ll often wait three
days, but there really are no good data.”

What about patients with an ejection fraction of less than 35%? According to the WARCEF trial
published in the May 17, 2012, NEJM, antiplatelet therapy for such patients is just as good as
anticoagulation, although long-term follow-up will be important to see.

As for PFOs, recent studies indicate that “endovascular closure doesn’t work better than medical
therapy and that antiplatelets are just as good as anticoagulants,” Dr. Josephson pointed out. “So
these patients are off the list of patients who require anticoagulation.”

It may make sense to use anticoagulants for three months in patients with vertebral or carotid
dissection, a common cause of stroke in younger patients, before switching to antiplatelets. “But
there are no good randomized data to drive this choice,” he said.

As for short-term anticoagulation, should hospitalists start a fib patients on heparin right away?

“The answer is no,” explained Dr. Josephson, “and there are now good data on that.” An analysis
published in the June 2013 Lancet Neurology looked at the largest trials of heparin, heparinoids
and low-molecular-weight heparin in acute stroke.

“Researchers found no benefit in any patient population, even those with the lowest risk of
bleeding and the highest risk of recurrent stroke,” he said. “Heparin is out, as least in most causes
of acute arterial stroke.”

As for the newer oral anticoagulants, Dr. Josephson said their use may lead to more a fib patients
being anticoagulated. But the new agents come with some stroke-specific concerns.

For one, the agents have little data supporting acute secondary prevention. “What we tend to do
is start patients on warfarin, then switch over to a new agent after a month or so until data
regarding their safety in the acute period are available,” he said.

And “IV tPA is absolutely contraindicated” in patients taking a new oral agent, he pointed out.
“They may be able to still get a mechanical embolectomy.” Plus, reversal with one of the new
agents “is a huge issue if somebody comes in with an intracerebral hemorrhage, until specific
reversal agents are available.”

Antiplatelet options
In terms of antiplatelet therapy, physicians have three options. There’s aspirin, and “in stroke, the
dose is not important between 81 mg and 325 mg,” said Dr. Josephson.

There’s Aggrenox, which patients take twice a day. “About 30% get a nasty headache so they
can’t tolerate it, but it’s an effective drug that’s marginally better than aspirin,” he said.

Clopidogrel is likewise marginally better than aspirin. But one of the largest trials in the field that
compared Aggrenox and clopidogrel in terms of secondary stroke prevention found “absolutely no
difference between the two,” he noted. “They’re both equally effective.” Because clopidogrel is
now generic, “it’s cheaper and it’s once a day, so we tend to use a little bit more of it.”
With stroke patients not already on antiplatelets, Dr. Josephson says he starts them on any one of
the three. For patients who have a stroke while taking aspirin, he stops the aspirin and prescribes
either Aggrenox or clopidogrel.

Could there be any advantage to combining clopidogrel and aspirin? There may be in the acute
period, according to research published in the July 4, 2013, NEJM. Chinese researchers tested the
combination for 90 days in patients who’d had an acute minor stroke or TIA.

“There were some very impressive results,” Dr. Josephson said. “The combination was better than
Plavix alone, and the number needed to treat to prevent one additional stroke was 29.”

Those results aren’t yet ready for prime time, he added, because the trial’s patient population was
so specific. “But a large North American trial that will be released in a few years is looking at the
exact same thing.”

Permissive hypertension
As for other therapies, “just about everyone gets a statin,” he said. “We give 80 mg of
atorvastatin to everyone with an LDL greater than 100. Any other statin probably works, as long
as it’s at high dose.”

Dr. Josephson also recommended tight glucose and fever control. “Hyperglycemia and high
temperature are really bad for the brain, so we like to control them,” he explained. And
enoxaparin is the “treatment of choice” for DVT prophylaxis. “It’s better than unfractionated
heparin, so we use it in all patients on the first day after ischemic stroke, with the exception of
those who received tPA.” For those patients, “we typically wait 24 hours.”

Then there is the issue of permissive hypertension. “The most common error I see people make
with acute stroke is lowering blood pressure,” Dr. Josephson said. “According to national
guidelines, we should allow blood pressure to go as high as 220 systolic before we touch it in
acute stroke, outside of tPA administration.” High blood pressure, he explained, delivers more
blood flow to ischemic regions. “Dropping it is associated with increased morbidity and worse
neurologic outcomes.”

Patients who’ve been given IV tPA are the one exception “but only because the trials establishing
the efficacy of that treatment “kept blood pressure at less than 18. Researchers felt that higher
levels would perhaps lead to more bleeding,” said Dr. Josephson. “We all keep blood pressure with
tPA below 185 for the first 24 hours, but there are not really good data to support that.”

For patients who come in on anti-hypertensives, “we stop those in the acute period with the
exception of beta-blockers, which we usually give at half dose,” he noted. What is controversial is
how long to let the permissive hypertension ride.
“We have no data,” he said, “but about 72 hours out or before patients go home, we start them
on one blood pressure agent, usually a thiazide or ACE inhibitor because those have better
secondary prevention data.” Doctors should then aim for normotension in concert with the primary
care physician over the next few weeks.

Treating TIAs aggressively

Another major development in stroke care over the past several years is recognizing that TIA
patients have “conceptually the same disorder as stroke and need the exact same work-up and
treatment,” Dr. Josephson pointed out. In fact, up to one-third of TIA patients will have an infarct
on their MRI scan.

“TIA is our version of unstable angina, and we should be uber-aggressive with these patients,” he
said. Studies have found that treating TIA aggressively can reduce patients’ stroke risk by 75%.

As for carotid stenosis, which can be the culprit in TIA or stroke, the CREST trail published in the
July 1, 2010, NEJM, produced this headline: Stenting is just as good as endarterectomy.

“But the stenting group had a much higher risk of stroke, while the endarterectomy group had a
much higher risk of MI, although the endpoints were similar after 90 days,” Dr. Josephson pointed
out. A meta-analysis of CREST data published online last October by JAMA Surgery confirmed one
interesting observation: People older than 70 with carotid stenosis did much better with
endarterectomy.

Why? “Presumably with stenting, you’re going with a catheter through some tortuous vessels that
have lots of atherosclerosis, leading to a higher stroke rate,” he explained.

In his practice, for anyone with a carotid stenosis more than 70% on the same side as a stroke or
TIA, “we revascularize. If they’re older than 70, we always do endarterectomy unless they are
very high risk.” For younger patients, “there is a reasonable argument for doing either procedure,
and we go through a risk/ benefit analysis for individual patients.”

As for the timing of revascularization, “data suggest that you should revascularize a patient with a
non-disabling stroke within two weeks,” he said. “We usually do it as early as that day for TIA
patients or those with minor stroke.”

“The whole idea of ‘let’s let them cool off for a month or two’ is out,” said Dr. Josephson. “It’s been
shown that most of the early benefit of revascularization is early on. The longer you wait, the
worse these patients do.”

Phyllis Maguire is Executive Editor of Todays Hospitalist.

Diagnosing the source

HOW SHOULD HOSPITALISTS work up ischemic stroke patients to identify the source of an
embolus?

To find a cardioembolic source, S. Andrew Josephson, MD, who heads up the neurohospitalist
program at University of California, San Francisco (UCSF), relies on 48 hours of telemetry as well
as an echocardiogram with a bubble study. And when it comes to which echocardiogram to order,
many prefer a TEE.

In a presentation on acute stroke treatment at UCSF’s man- agement of the hospitalized patient
conference last fall, Dr. Jo- sephson said that TEE is “the best echocardiographic method to look at
the arch,” adding that the aortic arch is “a common source of atherosclerosis, especially in
Caucasians. And a TEE provides a better look at the left atrial appendage.”

At UCSF, what Dr. Josephson called “the non-evidence- based truce with our cardiologists” is a
protocol that calls for a TEE in all stroke patients younger than 55. “These individu- als have a
higher incidence of having a cardiac source,” he ex- plained. For patients older than 55, Dr.
Josephson said, “we’ll perform a TTE first and then consider a TEE.”

Carotids should be evaluated with ultrasound, CTA, MR an- giogram or angiogram. And it’s
important to keep in mind that Asian Americans and others have a high incidence of intracra- nial
atherosclerosis, which also can be the source of stroke.

“You can look at these intracranial vessels with a CTA, an MRA or an angio,” Dr. Josephson said.

Physicians also need to consider patients’ stroke risk factors when trying to identify an embolus
source. But he noted that the so-called “stroke labs” are rarely helpful.

“If you find a stroke from a B-12 deficiency, give me a call,” he said. “I don’t know how these labs
started, but you can stop them apparently.”

What may help pinpoint where an embolus came from is extended cardiac telemetry. Between
20% and 25% of stroke patients leave the hospital with “cryptogenic strokes,” Dr. Jo- sephson
said. Those are strokes for which doctors haven’t been able to find any source but which appear
to be embolic.

“If you put those people on three to four weeks of continuous Holter monitoring, you find that
about 20% actually have a fib, which wasn’t apparent with telemetry and which clearly changes
management,” Dr. Josephson said. “We do this in everyone who leaves the hospital when we don’t
know why they had a stroke.”