Barnes-Jewish Hospital | Washington University Physicians
HISTORY | 
milestones from the archives

STROKE CARE AND TPA: A BACK STORY

EMCO
By Andrea Mongler

It’s 1982, and a man is having a heart attack. An ambulance rushes him to the emergency department, where he’s given a nitroglycerin tablet and a drug called nifedipine.

The treatment doesn’t seem to work, and the man’s heart sustains serious damage. An emergency physician delivers the news to the man’s family: “He might not survive the night. We’ll keep him comfortable, but there’s nothing else we can do.”

For years, this scene was a common one, played out again and again in emergency departments across the nation. Physicians did their best to care for heart attack patients—but their best too often wasn’t enough. That’s because nifedipine and other drugs used at the time simply weren’t effective.

Then, in 1983, everything changed. A team of Washington University specialists at Barnes Hospital—now Barnes-Jewish—treated a heart-attack patient with a new drug called tissue plasminogen activator, or tPA, and it worked. The team would go on to successfully treat several more people with heart attack, and tPA would soon be FDA-approved and widely used.

Today, tPA is no longer the standard of care for people experiencing a heart attack, though it is still used as a life-saving treatment in some cases. But early tPA research done at Washington University School of Medicine helped identify tPA as a highly effective stroke treatment.

“When I was a medical intern in the early ’80s, the damage done by a myocardial infarction [heart attack] was dramatic and mortality was high,” says Richard Bach, MD, FACC, Washington University cardiologist at Barnes-Jewish Hospital and Cardiac Intensive Care Unit medical director. “All these years later, I’m still amazed that advances in rapid effective treatments mean that most myocardial infarction patients are routinely stabilized so quickly that I don’t think our current trainees even appreciate how bad it once was. That’s remarkable progress.”

Developing tPA

The origin story for tPA includes Jewish Hospital (later to become Barnes-Jewish), with pioneering work done in the 1950s by a man named Sol Sherry, director of the hospital’s Division of Medicine. Specifically, Sherry helped develop a drug called streptokinase. Part of a drug class called thrombolytics, streptokinase breaks up a protein that’s one of the major components of blood clots.

Researchers studied the use of streptokinase in treating heart attack and found that it improved survival, which was a landmark advance. But it didn’t work as well as they hoped—and it could cause serious side effects, including allergic reactions and bleeding complications. Still, Sherry’s work was important because he was the first to suggest that thrombolytics could be used to treat heart attacks. At the time of his research, the link between blood clots and heart attacks was an unproven hypothesis.

In the 1970s and early ’80s, a group of researchers at Washington University School of Medicine, including Burton Sobel, worked with Belgian scientist Desire Collen to develop a thrombolytic drug using melanoma cells. Why use cells from cancer? Because Collen had found that melanoma cells, which produce large amounts of tPA, could dissolve blood clots when grown in tissue cultures. He quickly understood tPA’s potential to dissolve clots in patients.

“In the ‘70s, the idea that heart attacks were caused by a clot in a heart artery was viewed as a hypothesis, and there were debates about it among experts,” Bach says. “Burt Sobel was responsible for some of the most important early research showing that clots in heart arteries indeed were the cause of heart attacks and that it made perfect sense to test tPA in heart attack patients. He ended up spearheading a landmark clinical trial that led to a revolution in treatment of heart attacks.”

Proving that ‘tPA saved lives’

Prior to publication of that landmark trial, Sobel and colleagues had tested tPA in dogs with positive results. Then they were presented with an opportunity: A man had arrived at Barnes Hospital with symptoms of a severe heart attack.

Philip Ludbrook, MD, professor emeritus of medicine and psychiatry at Washington University School of Medicine, and a member of the original clinical-trial team, recounts the story in A Legacy of Caring: The History of Barnes-Jewish Hospital:

“It was the middle of the night, and [the patient] was the picture of severe pain. We said, ‘We don’t know whether this will work, we don’t know the exact dose, and we don’t know for sure whether it will transmit cancer [since tPA was developed from melanoma cells]. But it’s the only thing we can offer you to get out of this terrible heart attack.”

The patient agreed—and the treatment worked. It dissolved the clot responsible for the heart attack, and the patient recovered.

The clinical-trial team at Barnes and collaborating investigators at Catholic University of Leuven in Belgium would go on to treat six additional patients with tPA. In all but one of those patients, the treatment worked, dissolving the clot and restoring blood flow. A larger trial—with similarly positive results—came next, followed by a randomized trial comparing tPA to streptokinase. This research showed that tPA, compared with streptokinase, was a superior treatment for breaking up blood clots.

“Burt Sobel, Philip Ludbrook and their colleagues were pioneers in the field,” Bach says. “Not only did they prove the hypothesis that heart attacks are caused by clots in a heart artery, but they also showed that tPA saved lives. And while tPA is no longer the standard treatment for heart attack, we wouldn’t have made the advances that occurred over the following decades without their work.”

New options for heart-attack treatment

Once tPA became widely adopted for heart attack care, it saved many lives. Continuing research, however, would show that tPA wasn’t quite as effective as hoped. Though it was superior to earlier treatments, it broke up only 50% to 70% of clots in heart arteries. But because tPA had helped researchers understand the cause of heart attacks, it helped lead them to a treatment method called balloon angioplasty, a safer and more effective option.

Here's how balloon angioplasty works: A cardiologist inserts a catheter into the blocked artery. Once the catheter is in place, a balloon located at the tip of the catheter is inflated, which pushes the blood clot against the artery wall, thus restoring blood flow. A recent improvement to this treatment includes use of a stent, which is put into place after the balloon is deflated and remains in the artery to continue to ensure blood flow.

“We’ve come a long way since the mid-’80s, when the hypothesis that clots inside arteries caused heart attacks was confirmed, and we learned that a treatment to break up clots could abort heart attacks,” Bach says. “That work led to a better and faster and safer treatment through balloon angioplasty and stenting of the artery. Had the thrombolytic trials never been done, the advances we’ve seen since then may not have happened.”

Specialists continue to use tPA for heart attack in certain cases. Specifically, it can be used to treat someone who won’t be able to have balloon angioplasty within two hours of arrival at the hospital. The longer the delay in treatment, the more damage to the heart and the higher the risk of death; administering tPA can help minimize those risks.

Bach says most hospitals that don’t have the capability to perform angioplasty and stenting on site do have rapid-transfer protocols to get patients to another hospital as fast as possible. But certain factors can interfere with that two-hour window: bad weather, for example, or the distance from one hospital to the next. In those cases, guidelines recommend administering tPA, or a newer agent derived from tPA, to open the artery. Once treated, the patient then can be scheduled for angioplasty and stenting.

Other medical conditions can be treated with tPA as well. For example, it’s used to treat pulmonary embolism—a life-threatening condition in which a blood clot travels to the lungs—and to break up clots in dialysis fistulas and in IV catheters.

But tPA’s primary use today is as a treatment for ischemic stroke.

tPA as stroke treatment

Similar to heart attack, ischemic stroke is caused by a clot that blocks blood flow to the brain. And the history of ischemic stroke treatment is strikingly similar to that of heart attack treatment.

Until the mid-1990s, treatment options for a person who had arrived in the emergency department with a stroke were limited. Aspirin might be given to thin the blood, but there wasn’t much else to be done. Jin-Moo Lee, MD, PhD, Washington University neurologist at Barnes-Jewish Hospital notes that there was a time when “stroke was considered a non-emergency.” Lee also is head of the university’s Department of Neurology.

Washington University emergency medicine specialist Peter Panagos, MD, FACEP, FAHA, puts it this way: “There was no sense of urgency or rush. Whatever happened was left up to fate.”

But in December 1995, “everything changed,” Panagos adds. That’s when a multidisciplinary team of researchers published a study in the New England Journal of Medicine, which showed that tPA, given within three hours of stroke onset, improved outcomes for patients three months later. The study was a two-part randomized controlled trial in which patients (291 in part 1 and 333 in part 2) received either tPA or placebo. The study showed that patients treated with tPA were at least 30% more likely to have minimal or no disability after three months of stroke onset compared with patients who received placebo.

In 1996, the FDA approved tPA for use in stroke patients, though widespread use in hospital emergency departments happened more slowly. Lee says use of tPA increased sharply once the Centers for Medicare & Medicaid Services approved it for reimbursement, which “speaks to the importance of alignment with best clinical practice.”

But even then, many emergency departments didn’t adopt use of tPA for stroke patients right away.

“Neurologists for the first time were encouraging use of tPA for stroke patients in the emergency department, but there was resistance early on,” Panagos says. “That’s because there was a lack of education about tPA, clinicians were unfamiliar with it, and many emergency departments didn’t have the systems in place to use tPA to treat people with stroke.”

Before long, though, use of tPA “snowballed,” he says, with larger academic hospitals taking the lead and others following. Soon, the American Heart Association spearheaded an initiative to form “stroke centers”—medical centers with physicians specially trained in emergency stroke care—and the Joint Commission (the organization that accredits hospitals) began certifying some hospitals as Primary Stroke Centers.

Within a few years, the number of hospitals certified as Primary Stroke Centers had grown dramatically. Smaller, uncertified hospitals began to routinely send stroke patients to nearby certified centers. Among researchers, the focus shifted from whether to use tPA at all to the timeframe in which to use it.

The stroke-treatment window

Though tPA is a lifesaving treatment for many stroke patients, its ability to dissolve clots carries a serious risk: hemorrhage, or bleeding in the brain. That means physicians must carefully weigh the potential benefit of administering tPA—a reduced risk of neurologic damage and disability—with the risk of a potentially life-threatening hemorrhage.

In general terms, the equation is something like this: If tPA is given early enough, its effect can be so beneficial that the risk of hemorrhage is worth the benefit. But if the length of time between stroke onset and receipt of tPA is too long, damage from the stroke may already have been done, making the risk of hemorrhage an unnecessary one. And the risk of hemorrhage goes up as each hour passes after stroke onset.

“The brain is very unforgiving to the lack of blood flow caused by a clot,” Panagos says. “It starts to die very quickly. We know we need to give tPA as soon as possible after symptom onset. The question is: At what time point does the benefit of giving tPA no longer outweigh the risk?”

The study published in 1995 study showed that about 6% of participants given tPA within three hours of stroke onset experienced bleeding in the brain, compared with only 0.6% given placebo. That three-hour window became standard practice: Patients who were within three hours of onset would receive tPA; those past the three-hour mark likely would not.

Since that study, researchers have continued to evaluate the timing of tPA treatment with the goal of giving as many stroke patients as possible the chance to safely receive a lifesaving treatment. In the early 2000s, a few trials in Europe found that administering tPA up to 4.5 hours after stroke onset may be beneficial for certain patients. And a few years ago, other studies used MRI imaging to show that it may be possible for some people with “wake-up stroke” can safely receive tPA up to 24 hours after symptom onset. A wake-up stroke is one that occurs during sleep; when the person wakes, symptoms are noticed but there’s no way to know when they started.

Panagos notes that the expanding the window for tPA treatment is another way to demonstrate how stroke care has “changed dramatically.” He says: “There was no effective acute treatment available in the history of mankind until 1996, when tPA was approved. And then, over the last 25 years, there really has been a revolution in stroke care.”

Saving “so many countless lives”

Researchers continue to look at innovative uses of tPA. For example: After publication of several groundbreaking clinical trials, it has become the standard of care to use tPA in combination with mechanical thrombectomy, which uses a catheter to remove the blood clot if it is located in a large artery. While this treatment combination isn’t indicated for every person with stroke, researchers have demonstrated that it can minimize adverse outcomes in some. 

Researchers also are studying a thrombolytic drug called tenecteplase, or TNKase. Like tPA, TNKase breaks up clots. But TNKase is given quickly in a single injection, while tPA is given intravenously over the course of an hour.

These advances, of course, build on the first studies looking at tPA as a stroke treatment. And those studies were a direct result of the research showing that tPA could successfully treat clots in people with heart attacks.

“It’s incredible to think back on the development of tPA and its initial use in heart attack patients at Barnes Hospital, given what we now know this work would lead to,” Bach says. “It was pivotal and very, very important in the history of medicine. And it turned out to be a venture that would save so many countless lives over the years.”


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