Q: How is tissue plasminogen activator (t-PA) used to treat brain attack?

For a number of years, t-PA (Activase® Alteplase) has been used in the treatment of acute myocardial infarction. The U.S. Food and Drug Administration (FDA) has approved the use of t-PA to reestablish blood supply to tissue damaged in an acute ischemic stroke. In the United States, a two-part double-blind placebo controlled trial conducted by the NINDS has provided a framework for patient selection and treatment protocols for brain attack.

Part I of the NINDS trial compared neurological outcomes at 24 hours among patients given t-PA with the outcomes of a placebo group. Patients in the study group were given t-PA within three hours after the onset of symptoms. Part II assessed patient outcomes three months after treatment with t-PA. The study found no significant neurological improvement in 24 hours among patients who received t-PA as compared with the placebo group. However, at three months, patients in the t-PA group were at least 30 percent more likely than those in the placebo group to have little or no disability. Degree of disability was determined using four well-established measures: the Barthel index, modified Rankin scale, Glasgow outcome scale, and the National Institutes of Health Stroke Scale.

NINDS protocol emphasized careful patient selection to prevent administration of t-PA to patients experiencing a hemorrhagic brain attack and others who may be at risk of excessive bleeding. Under NINDS protocol, approximately 3 percent of all patients presenting with stroke symptoms were eligible for the study. This includes eligible patients who declined treatment. Although estimates of the percentage of patients eligible for t-PA therapy under this protocol vary, t-PA will likely continue to be a beneficial therapy for a relatively small percentage of brain attack victims. The Stroke Council of the AHA issued the following guidelines for thrombolytic therapy in acute brain attack based largely on the protocols used in the NINDS trials.

Hemorrhage resulting from treatment with t-PA is a concern even under this protocol. In the NINDS study, 6.4 percent of patients in the t-PA group had symptomatic hemorrhage in the head within 36 hours after the onset of brain attack symptoms. The rate was 0.6 percent in the placebo group. Rates of asymptomatic hemorrhage were similar in the two groups.

In Minnesota, a collaborative study called Stroke Treatment in the Community or the STIC program has begun. The overall purpose of the STIC program is to learn whether the benefits and risks of treatment with t-PA in Minnesota match that of the NINDS study. This will be determined by monitoring the results of brain attack treatment. Monitoring includes assessments of:

• How often hemorrhage occurs in patients treated with t-PA.
• Clinical outcome and mortality of patients at three months.
• Whether factors such as age, brain attack severity, or aspirin use affect the rate of hemorrhage.
• The ability of physicians to interpret CT scan findings. How closely community physicians follow treatment guidelines outlined by the NINDS.

Q: What costs are associated with t-PA treatment?

Treatment of an ischemic stroke with t-PA is covered by health plans when the appropriate protocol is followed. Medicare and Medicaid also cover treatment of an ischemic stroke with t-PA if the appropriate protocols are followed. However, the direct and indirect costs of t-PA treatment for brain attack are a concern. Direct costs include the costs of the drug itself and the CT scan necessary to rule out hemorrhage.

Current protocol recommends patients receiving t-PA be admitted to an intensive care unit for the first 24 to 36 hours after treatment, during which patients are monitored for signs of hemorrhage in or around the brain. Additional costs are incurred if patients develop complications due to hemorrhage.

Many community hospitals do not have a system in place that coordinates hospital-based and emergency medical services to support treatment of patients with t-PA. Indirect costs of treatment include development of coordinated systems and training professionals involved in the continuum of care necessary to effectively treat brain attack victims. Professionals include those on nurse care telephone lines, emergency medical personnel who transport brain attack patients and hospital-based personnel who care for these patients. Indirect costs are associated with 24-hour availability of physicians trained in interpreting CT scans for brain attack and ready availability of neurologists or other professionals who can identify and treat complications from the treatment.

Treatment of ischemic brain attack offers potential long-term benefits to patients along with cost savings to individuals and society. In the United States direct medical costs and lost productivity related to brain attack amounts to approximately $30 billion each year. Patients for whom t-PA minimizes tissue damage need little or no extensive rehabilitation or care in a skilled nursing facility. These two components are large portions of the cost associated with the aftermath of brain attack.

Q: What issues are involved in the use of t-PA?

Administration of t-PA, and possibly other therapies in the future, present opportunities to treat brain attack before permanent neurological damage occurs. However, a medical infrastructure that allows safe, timely diagnosis and treatment of brain attack is necessary if t-PA is to be successfully used in community hospitals. This infrastructure includes public awareness about brain attack, training physicians and other personnel in prompt identification of brain attack emergency medical services (EMS) response and personnel and equipment needed to identify and treat brain attack.

Q: What are unresolved issues in the treatment of brain attack?

T-PA is the only treatment for brain attack approved by the U.S. Food and Drug Administration (FDA). Research is underway on a number of other drugs administered either with or instead of t-PA that may reduce tissue damage during a brain attack. However, their clinical effectiveness has not been proven. Neuroprotective agents are one group of these drugs under study. These compounds either protect the brain tissue from damage or promote repair of brain tissue affected by blood and oxygen loss. One type of neuroprotector, citicoline, is currently part of a clinical trial in the United States, and is available for use in Europe and Japan.

Views of brain attack as a treatable condition will continue to evolve as treatment protocols develop. Continuing research on brain attack may resolve issues about whether new treatments will reduce the need for a CT scan to rule out hemorrhage. Another issue to be resolved is whether new therapies might allow for effective treatment of brain attack outside the three-hour time window. A medical system to support prompt and effective assessment and treatment of stroke must also be in place for potential future treatments.

Q: How can the incidence of brain attack be decreased?

The incidence of brain attack may be decreased through several strategies. Some risk factors for brain attack cannot be modified. These include age, gender and race. However, some risk factors can be modified. Brain attack risk factors which can be modified or treated include smoking cigarettes, physical inactivity, high blood pressure, diabetes, and heart disease. These risks may be reduced through behavioral and medical care changes including management of diabetes, control of high blood pressure or heart disease, and smoking cessation.

Patients who have one or more risk factors for brain attack should be encouraged to talk with their physician or other health care practitioners about ways they could reduce their risk.