Approximately 700,000 strokes occur annually in the United States.1 Eighty percent of these strokes are ischemic in etiology. Acute ischemic stroke has devastating effects on the health of our society. Stroke ranks only behind heart disease and cancer as a cause of death. In addition, stroke is the leading cause of serious, long-term adult disability in this country.2 These negative health effects of stroke have been the impetus to develop acute therapies that can salvage brain tissue soon after stroke onset. This article will review the only approved interventional therapy for ischemic stroke: intravenous adminstration of tissue plasminogen activator (tPA). The clinical development, applications, and implications of this stroke therapy will be discussed.
Focal brain ischemia is a dynamic event. An ischemic core, in which no blood flow is present, comprises a small area distal to an arterial occlusion. Between brain regions receiving normal perfusion and this ischemic core is an intermediate area called the penumbra. Within the penumbra, blood flow is reduced to a level that stuns neurons and interrupts their function. Initially neurons in the penumbra can maintain their integrity by keeping ATP levels near normal. If perfusion does not return to normal levels, these neurons eventually loose their ability to preserve ATP generation. The duration of time during which the penumbra remains viable depends on the degree of blood flow reduction. Animal models suggest that the penumbra can remain viable for only a few hours if normal blood flow is not restored.
Since brain tissue within the penumbra is salvageable, the potential exists for altering the final outcome from focal brain ischemia. Most brain infarctions are due to an arterial occlusion. For nearly forty years there has been experimental interest in using thrombolytic drugs to open symptomatic cerebrovascular arterial occlusions. The first randomized trial to investigate the efficacy of a thrombolytic drug for treatment of stroke was published in 1963.3 Six other randomized trials were conducted between 1963 and 1992.4-9 No conclusions could be drawn from these trials due to their small sizes (726 people were randomized into all trials), wide range of symptom duration prior to treatment (less than 3 hours to less than 30 days), diversity of drugs (tPA, urokinase, streptokinase, and fibrinolysin), and diverse outcome measures. Two of these studies were conducted prior to the advent of CT.
Although these trials did not demonstrate efficacy, three of the trials that were conducted in the early 1990s7-9 demonstrated that it was feasible to conduct a large, randomized study of early thrombolysis. The pivotal trial that demonstrated efficacy was conducted at eight clinical centers with funding from The National Institute of Neurological Disorders and Stroke (NINDS).10 The thrombolytic drug utilized in this study was tPA. TPA's thrombolytic effects are mediated by plasminogen. After attaching itself to vascular clots, tPA activates plasminogen. Plasminogen degrades fibrin in the clot, leading to clot dissolution.
The NINDS study was double-blind and placebo-controlled. This study was actually two independent trials, designated part 1 and part 2. With the exception of the primary and secondary outcome measures, the protocols for both parts were identical. Part 1 examined short-term neurological improvement by testing the hypothesis that clinically meaningful improvement would be measurable within 24 hours following treatment. A secondary hypothesis was that tPA treated patients would show sustained improvement at 3 months. A tPA dose of 0.9 mg/kg was utilized, not to exceed 90 mg/kg. Ten percent of the dose was administered intravenously over one minute, with the remainder infused over one hour. Heparin and aspirin were not given concurrently with tPA. Patients were eligible if they were 18 years or older, had a clinical diagnosis of ischemic stroke, a clearly defined onset of symptoms less than 180 minutes prior to treatment, and a CT scan showing no evidence of intracranial hemorrhage. Exclusion criteria are listed in Table 1. Patients with an initial blood pressure exceeding inclusion thresholds could be enrolled into the study if their blood pressure responded to nitropaste or a dose of intravenous labetolol. In part 1, 67 (47%) of the 144 patients randomized to tPA had early improvement compared with 57 (39%) of the 147 patients randomized to placebo (p=0.21).
Table 1. NINDS tPA Trial Exclusion Criteria |
| Rapidly improving or
minor symptoms Seizure at symptom onset Any history of intracerebral hemorrhage GI or any serious hemorrhage within 3 weeks Major surgery or trauma within 2 weeks Arterial puncture at a noncompressible site within 7 days Stroke or head trauma within 3 months Clinical history suggesting subarachnoid hemorrhage Systolic BP >185 or diastolic BP >110 Protime >15 Received heparin within 48 hours and PTT is elevated Platelet count <100,000 Blood glucose <50mg/dl or >400mg/dl Presumed septic embolus |
During the final interim analysis for part 1, the NINDS trial Data and Safety Monitoring Committee determined that the three month outcome measures for the patients in Part 1 favored the tPA treated group. The committee recommended that a second trial (Part 2) commence to test the primary hypothesis that there would be a significant difference between the tPA and placebo groups in the proportion of patients who recovered with no or minimal deficit at 3 months after treatment. Four validated scales were utilized to measure clinical outcome from stroke. The NIH Stroke Score is a 42-point scale that quantifies neurologic deficits. The Barthel Index is a 100-point scale that measures ability to perform activities of daily living. The modified Rankin and Glasgow outcome scales are simplified assessments of patient function. Outcome was assessed at 3 months post randomization. The absolute difference in favorable outcome of tPA versus placebo was 11-13% across the scales (Figure 1). Depending upon the scale, the increase in relative frequency of favorable outcome in patients receiving tPA ranged from 33% to 55%. The effect of tPA was independent of stroke subtype with beneficial effects seen in those with small vessel occlusive, large vessel occlusive and cardio-embolic induced ischemia.
In the NINDS trial, intracerebral hemorrhage (ICH) occurred
more frequently in tPA treated patients. Approximately
6% of the r-tPa treated patients sustained a symptomatic ICH
within 36 hours following treatment compared with 0.6% of
patients receiving placebo. Half of the tPA associated
symptomatic hemorrhages were fatal, however tPA treatment was not
associated with an increase in mortality in the three-month
outcome analysis. A multivariable analysis conducted by the NINDS
investigators determined that severe baseline neurological
deficit (NIH stroke score >20) and clear signs of brain edema
or mass effect on the pretreatment CT were independent risk
factors for intracerebral hemorrhage.11
Several other randomized, multi-center, placebo-controlled trials examining the efficacy of intravenously delivered thrombolytic agents have recently been completed. The European Cooperative Acute Stroke Study (ECASS) was a trial using 1.1 mg/kg of tPA or placebo in 620 patients with stroke symptoms that were less than 6 hours in duration.12 This trial showed no benefit for tPA in the intent-to-treat analysis and a higher mortality rate in tPA treated patients (18.9% vs. 15.8%) at 3 months. A subgroup analysis, in which 109 protocol violators were excluded, was performed on the remaining target population of 511 patients. The target population analysis revealed better three-month outcome in the tPA treated patients on one of the two outcome measures. The most common enrollment violation was an initial CT showing sulcal effacement or a hypodensity in more than one-third of the middle cerebral artery territory (Figure 1). Those patients with large regions of early ischemic change on the baseline CT who were treated with tPA were more likely to have a poor outcome and have an ICH than those patients who received placebo.
|
Figure 1. Non-contrast brain CT scan of an early middle cerebral artery distribution infarction. Loss of sulcal differentiation and a hypodensity are present in the left cerebral hemisphere (arrows). The presence of these radiographic findings is a contra-indication to tPA administration. |
Three trials investigating streptokinase have been conducted.13-15 Enrollment in all three trials was terminated prematurely due to an unfavorable risk-benefit profile in the actively treated populations. The negative results of ECASS and these streptokinase trials do not annul the positive results of the NINDS tPA trial. Several fundamental differences in trial structure exist between the NINDS trial and the other trials. These differences have been extensively reviewed elsewhere.16 Major differences include a shorter median time to treatment and lower rate of ICH in the NINDS trial.
Intravenous tPA has proven efficacy in the clinical trial setting. The beneficial effects of tPA are being replicated in clinical practice and outcome following treatment with intravenous tPA appears to be consistent with data reported by the NINDS investigators. A recent prospective multi-center evaluation of 75 tPA treated patients reported that 34% of patients had an excellent outcome. The rate of symptomatic intracerebral hemorrhage in this cohort was 7%.17 The benefits of TPA also appear to be durable. A follow-up study conducted by the NINDS investigators showed that patients treated with tPA were 30% more likely than placebo treated patients to have minimal or no disability at 6 months and 1 year, compatible with the findings reported at three months.18
In addition to improving patient outcome, treatment of acute ischemic stroke with tPA may result in a net cost savings to our health care system. Stroke is one of the most costly diseases afflicting Americans. Health care expenditure associated with stroke approach 40 billion dollars annually. Treating acute ischemic stroke with tPA has been estimated to produce a cost result in a net cost savings of 4 million dollars per 1000 patients treated.19 These savings are obtained primarily through less dollars spent on nursing home and rehabilitation costs.
Clearly there remains a need for other acute stroke therapies. Some patients who receive tPA still go on to have a disabling brain infarction. In addition, only a small minority of ischemic stroke patients is being treated with tPA. During the past two years, 3% of all stroke admissions to University Medical Center have received tPA. The most frequent reason for not administering tPA is presentation beyond three hours. Other reasons for not utilizing thrombolytic therapy are presence of medical exclusions (Table 1), severe stroke defined by a NIH Stroke Score >22, or radiographic evidence of hemorrhage or an early, large middle cerebral artery distribution infarction.
Challenges for the future are to raise public knowledge about emergency therapy of stroke and to develop other inter-ventional therapies that magnify the beneficial effects of tPA. Patient delays in seeking treatment following onset of stroke symptoms is probably due to a relatively low level of public awareness about stroke. In a survey conducted by the National Stroke Association, 40% of those polled did not know any warning signs of stroke.20 Educational campaigns aimed at the public will play a major role in increasing stroke awareness. Other interventional therapies may soon be available to clinicians. Neuroprotective agents are drugs that interfere with cytotoxic biochemical cascades that occur in neurons when these cells are exposed to ischemia. Catheter delivered intra-arterial thrombolysis is currently in phase 3 clinical investigation. Whether these interventional therapies will supplement intravenous administration of tPA remains to be seen.
Vigorous scientific investigation has demonstrated that intravenous administration of tPA is an effective interventional therapy for impending ischemic stroke. The rate of neurologic recovery is modest, the risk of intracerebral hemorrhage is low, and mortality is not increased following thrombolytic therapy with tPA. Not all patients with symptoms of ischemic stroke can be treated with tPA. In order to minimize their risk of treatment asssociated intracerebral hemorrhage, patients must meet strict clinical and radiological criteria before receiving tPA. Development of other acute interventional therapies in the future may augment the benefits of this medication.
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