Underutilization of Tissue Plasminogen Activator in Acute Ischemic Stroke

Christopher M. Loar M.D.
Tissue Plasminogen Activator (T-PA) Expert Witness


Tissue Plasminogen Activator (T-PA, brand name Alteplase) is a medication that is given intravenously to dissolve blood clots.  It is the only scientifically proven, effective treatment for acute ischemic stroke (1). Its use has been shown to benefit more than half of individuals treated when given under appropriate circumstances and within a time period of 4 and 1/2 hours from the onset of stroke symptoms (2, 3, 9 ,10).  Yet, despite a proven safety profile, T-PA medication is given to only 3% to 8.5% of potentially eligible patients for treatment of acute ischemic stroke. (13) This underutilization of a proven treatment for acute ischemic stroke may lead to liability issues for doctors and hospitals.

The Early Development of T-PA for Stroke

T-PA was first confirmed in 1995 as a safe and effective drug for acute stroke in a study performed by the National Institute of Neurological Disorders and Stroke Study Group (NINDS) (1).  This study found that when T-PA was started within the first 3 hours from the onset of symptoms, patients were 30% more likely to have minimal or no disability at 3 month follow up when compared to patients who received a placebo.

An earlier study, however, had revealed that when T-PA was administered up to 6 hours from onset of acute stroke symptoms, there was an unacceptably high risk of hemorrhage in the brain and elsewhere in the body which caused more harm than good (6).  Hemorrhage was then recognized as a potential complication of the use of T-PA. The 1995 NINDS study (1) confirmed that the timing of T-PA use was a critical factor in mitigating the risk of hemorrhage.

In the 1995 NINDS study the authors established several inclusion and exclusion criteria to be certain that only true stroke patients were in the study group and to minimize the risk of brain hemorrhage.  The criteria excluded patients whose symptoms began more than 3 hours prior to presentation or whose symptoms or prior treatment would make them prone to develop hemorrhage. The criteria also eliminated other co-existing conditions that present with stroke-like symptoms such as weakness following a seizure.

The NINDS study recommended the following inclusionary criteria for the use of T-PA in acute ischemic stroke:

1. Age 18 or older

2. Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit presumed to be due to cerebral ischemia after CT brain scan excludes hemorrhage

3. Time of onset well established to be less than 180 minutes before treatment would begin

4. Informed consent must be obtained.

The NINDS study recommended the following exclusionary criteria for the use of T-PA in acute ischemic stroke:

1. Major symptoms that are rapidly improving by the time of treatment.

2. Evidence of brain hemorrhage on CT brain scan.

3. Hypodensity or mass effect suggestive of evolving infarction on CT brain scan.

4. Seizure at onset of stroke.

5. Clinical presentation that suggests subarachnoid hemorrhage (SAH), even if the initial CT brain scan is normal.

6. On repeated measure, systolic blood pressure greater 185, or diastolic blood pressure greater than 110 at the time treatment is to begin. May use IV medications to reduce blood pressure.

7. Persistently high blood pressure requiring overly aggressive treatment.

8.  Blood glucose of less than 50mg/dl or greater than 400mg/dl (test result required before treatment).

9.  Platelet count less than 100,000 (result required before treatment).

10. Prothrombin time greater than 15

11. Patient has received heparin within 48 hours and has an elevated partial thromboplastin time (PTT).

12. Patient is currently taking oral anticoagulants.

13. Major surgery or serious trauma in the previous 3 months.

14. History of gastrointestinal or urinary tract hemorrhage in previous 21 days.

15. Recent arterial puncture at a non-compressible site.

16. Lumbar puncture in the previous 7 days.

17. History of stroke or serious head trauma in the previous 3 months.

18. History of brain hemorrhage.

19. Clinical presentation consistent with acute myocardial infarction.

20. Clinical presentation suggesting post-myocardial infarction pericarditis.

21. Patient is a lactating female or known or suspected to be pregnant.

In the NINDS study the appropriate use of T-PA was defined as fulfilling inclusionary criteria (acute stroke within 3 hours of symptoms) and without evidence of exclusionary criteria. The NINDS study showed that the use of T-PA was effective and resulted in a 30% improvement in the chance of sustaining minimal or no disability at 3 month follow up over and above patients who received placebo or no treatment. This benefit was gained without an increase in mortality when compared with the placebo group. (1)

Independent re-analyses of the data from the NINDS study (9, 10) showed that t-PA treatment resulted in either complete neurologic recovery or improvement of stroke disability in over half of patients treated. In 2007 Demaerschalk (18) found that acute stroke patients treated with t-PA according to accepted protocol were at least 10 times more likely to be helped than harmed.

The effectiveness of T-PA has been validated by several more recent studies (2, 3) and the benefit has been more clearly realized.  An analysis was performed of the pooled data of all placebo-controlled trials of T-PA (8). That pooled data included 2776 patients and the results showed that 30% of patients who were treated with placebo had full recovery and about 40% had full, or nearly full, recovery at 3 month follow up.

Additional studies have shown that the window of opportunity to treat acute stroke could be safely extended to 4 and 1/2 hours without sustaining a greater risk of adverse side effects such as intracranial hemorrhage (2, 3).

Stroke Evaluation Protocol for t-PA Use

Hospitals and emergency rooms have increasingly been developing protocols to permit the rapid evaluation of stroke patients for timely administration of t-PA. The evaluation process must be able to determine if inclusionary criteria are met and verify the absence of exclusionary criteria. All of this must be performed rapidly because of the severe time constraints of the window of opportunity to treat with t-PA. Clinical examination must be done by a physician. A CT brain and laboratory studies must be done and the results made available quickly so that clinical decisions can be made as to the appropriateness of treatment with t-PA. And then informed consent is required. Because timing is so critical many facilities strive to meet a “door to needle” time of under 60 minutes. This means that the t-PA infusion is started within 60 minutes from the time that the patient arrives at the doorway of the treating facility. This is a challenge for almost all hospitals and emergency rooms and takes considerable coordination of multi-departmental resources.

Hazards of t-PA 

The NINDS study reported that 6.4% of T-PA treated patients sustained symptomatic brain hemorrhage compared to 0.6% of placebo patients (1). However this reported rate may be higher than clinically apparent (10, 11).  A reanalysis of the NINDS data (11) concluded that the NINDS authors had

[U]sed an extremely conservative protocol definition of clinical worsening, any deterioration in the patient’s neurologic condition, now generally recognized as inaccurate. Under this definition minor fluctuations in the patient’s course . . . were counted as symptomatic. . . . Only increase in examination score by a substantial degree could be taken as evidence of symptomatic decline. (11, p.2281)

The reanalysis showed that T-PA treatment will cause a meaningful clinical deterioration in only about 1% of patients treated with T-PA (7,11). The use of T-PA did not cause an increase in mortality. The NINDS study showed that 21% of placebo treated patients died by 3 month follow up compared with 17% deaths in T-PA patients at 3 month follow up, a difference that was not statistically significant. Thus there was no increase in the number of deaths attributable to T-PA treatment (1).

Current Utilization of t-PA

T-PA has been widely utilized for acute stroke in the US since 1995 and was approved for use in Europe in 2002 (4). Subsequent European studies have confirmed that the use of T-PA is as safe and effective in routine clinical practice as it is in randomized trials (5).  Studies in Europe also confirm that the use of T-PA is safe and effective when used within a 4-1/2 hour window of opportunity from the onset of acute stroke symptoms (2, 3)

Standard of Care

The use of T-PA in acute ischemic stroke cannot be said to be the widely accepted standard of care. The standard of care is defined as the care provided by a physician in good standing (11,12). Physicians are required to provide that level of care and skill that a physician in good standing would provide under the same circumstances. If a physician does not provide this care and if that event causes the patient injury or damages then the physician could be liable for damages to the patient.

Although t-PA has been shown to be beneficial with little risk of harm it is still infrequently used.

The literature shows that only 3% to 8.5% of potentially eligible patients are receiving T-PA (13).  Of the total, only 2% of eligible patients in community hospitals are receiving T-PA (14).

The frequency of TPA use in acute ischemic stroke may be affected by different viewpoints. There is one viewpoint that T-PA is safe and effective for acute stroke and is effective in routine clinical practice outside of controlled trials (5). However emergency physicians, who represent the first line of defense against acute stroke, may be resistant to the use of T-PA in stroke because of the perceived increased risk of adverse effects and lack of benefits. The educational guidelines of the American Academy of Emergency Medicine make the point that the risks of TPA use are great (15,16,17).

There is also a practical issue due to the difficulty in rapidly performing the evaluation and the coordination of multi-departmental hospital resources. This is an impediment to the wider use of this therapy.


Since T-PA use in acute ischemic stroke is not yet the widely accepted standard of care, it is important for treating physicians to communicate to patients and their family the risks and benefits of T-PA use through informed consent procedures. It is important that up-to date and accurate information be conveyed so that they can weigh the benefits versus risks of T-PA treatment. This is part of the standard of care. If this duty is breached, and if the breach causes the patient harm, then physicians may be liable for tort damages.

About the Author

Dr. Christopher M. Loar MD is a diplomate of psychiatry and neurology in neurology. He is a Tissue Plasminogen Activator (T-PA) Expert Witness, and can be reached at:  Phone: 281-359-4483  Email: cloar@drloar.com   Website: www.drloar.com


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