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Treating acute ischemic stroke

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.”