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  • 1 54 54
  • 2 54 54 In this lecture, we will discuss a clinical case that demonstrates the use of tPA in stroke, discuss the NINDS clinical trials that lead to tPA approval, discuss the results of the nine phase IV clinical trials that document clinical use of tPA, and discuss the significance of these data on the use of tPA in Emergency Department patients who present with an acute cerebrovascular accident (CVA).
  • 3 54 54 In this case presentation, it is evident that the patient has had an acute CVA. The symptoms are consistent with a middle cerebral CVA with a right-sided deficit. She is fortunate that she did it in a store, where 911 help was immediately obtained. This lead to the early transport to the Emergency Department. Because of her timely delivery to the Emergency Department, rapid evaluation, and the timely performance of a head CT, the patient was in the position to receive tPA in less than 90 minutes, well within the 180 minutes required by the NINDS clinical trials.
  • 3 54 54 The patient’s vital signs were good, with no evidence of an acute hypertensive emergency. The patient had neurologic deficits consistent with a middle cerebral artery occlusion and right sided findings. The presence of visual field neglect, facial weakness, extremity paralysis, without significant impairment in mental status suggests that the patient has an NIH stroke scale score in the 15-20 range, which is the range which is optimal for the use of tPA. A patient with an NIH stroke scale in this range has a stroke that is severe enough to require therapy, but is not so ill that the risk/benefit would defer tPA use. The patient’s estimated weight is needed in order to dose tPA in acute CVA patients.
  • 4 54 54 These are some of the questions that need to be addressed when considering the use of tPA in stroke. All are relevant to the practice of Emergency Physicians as they treat patients with an acute CVA. It is noteworthy that the results of the NINDS clinical trials provide only a part of the data required when considering the use of tPA in stroke patients.
  • 4 54 54 The phase IV studies of tPA in acute stroke patients must also be considered when deciding the use of tPA. Not only is clinical efficacy important, but effective use in clinical practice must also be analyzed for its impact on decision making in this setting.
  • 17 5 The main results of the NINDS clinical trials form the basis for our use of tPA in stroke patients. When tPA is used within 180 minutes of symptom onset, 30% more patients will have a good outcome at 90 days. Intra-cranial hemorrhage rates are three times greater with tPA use, with a rate of 11% in tPA-treated patients. Symptomatic intra-cranial hemorrhage rates (those that cause a deterioration in the patient’s neurologic status) are ten times greater with tPA use, with a rate of 6.4% in tPA-treated patients. Despite the fact that tPA-treated patients develop a greater number of cerebral hemorrhages, mortality at 90 days is the same with or without tPA use, which demonstrates the significant mortality risk of sustaining an acute CVA.
  • 17 5 When interpreting the NINDS results, it is necessary to understand the design issues that guided patient selection and the use of tPA. Patients with persistently elevated blood pressure, those whose BP required aggressive management in order to gain control, and those who received any anticoagulant in the past 48 hours (not daily ASA therapy) were excluded from the study. No further information was provided regarding these exclusion criteria. Following tPA administration, no anti-coagulants or anti-platelet drugs were to be given for 24 hours, and BP was to be controlled. No further information was provided regarding these post-infusion guidelines.
  • 44 54 54 The key results of the NINDS trials must be explained to the patient and any family members who are assisting in the decision to use tPA. This information must be documented in the medical record. The most difficult concept to explain involves the fact that mortality rates are comparable, despite a greater intra-cranial hemorrhage rates following tPA use. This data supports the notion that a patient who has sustained an acute CVA is ill and at risk for a grave outcome,with or without tPA therapy. Once a decision has been made either to use or not to use tPA, the Emergency Medicine physician must document the rationale for the decision in terms of the potential for benefit, the inherent risks, and the preferences expressed during the discussion with the patient and their families.
  • 44 54 54 Drug efficacy is established in clinical trials that follow set treatment protocols that minimize variation in the management of patients. When a drug is shown to be efficacious, this does not mean that will be effective when used outside of the rigors of a clinical trial. Effective clinical use suggests the a drug is efficacious even when used by many different Emergency Medicine physicians, in varied clinical settings, for patients who may not exactly match those in the efficacy trial, using treatment strategies that are not strictly controlled. In other words, can front line physicians reproduce the same results in clinical practice, which is not strictly controlled? If differences in outcome do occur, what are some of the potential causes of these differences?
  • 44 54 54 If differences in outcome do occur, there are many differences that can occur in clinical practice that lead to the altered efficacy. Differences in patient selection, intervention administration, concomitant therapy administration, and outcome measurement all can lead to the reporting of outcomes different than those seen in the NINDS clinical trials. All of these variables in some way relate to the expertise of the clinical practitioners in providing stroke care using tPA. What do the phase IV reports suggest are the reasons for differences from the NINDS efficacy study that may be observed?
  • 44 54 54 In the NINDS efficacy trials , the median NIHSS score was 14, which suggests that half of the patients in the study had mild to moderate stroke symptoms. Bear in mind that the NIHSS can be as high as 42, and that patients with a NIHSS score greater than 20 are considered to have a more severe stroke. The descriptions of two patients, one with an NIHSS score of 1, and the other with a score of 25, come directly from the methods in the NINDS publication. This information is critical, since NIHSS severity is a key element in assessing patient risk and the potential for benefit when using tPA, and when comparing the results of the NINDS clinical trials to the results observed in clinical practice.
  • 44 54 54 The other clinically relevant considerations fall into two major categories: the first is patient characteristics, and the second is the practice patterns within the institutions that deliver tPA. Age is an important consideration in assessing potential risk and benefit. Although there is no data to suggest that advanced age in and of itself increases risk when using tPA, the presence of co-morbid illnesses with advanced age does intuitively suggest that older patients are at greater risk with an acute illness such as stroke. Similarly, those who sustain a stroke at a younger age have the potential increased benefit of having a greater number of productive years if the effects of the acute stroke can be minimized. Assessing the size of the stroke can be achieved both by calculating the NIHSS (which, as it increases, correlates with a stroke of increasing brain vloume), and by directly examining the size of the low density area that corresponds to the likely infarct vessel (such as the middle cerebral artery). Stroke size is important when considering both the risk/benefit of using tPA and whether or not it should be used at all (large low density areas on the initial CT suggest a stroke of long duration, which might exclude its use due to the 180 time criteria). The timing of the tPA use within an institution will affect outcome in that the sooner that the tPA is given, the greater the likely benefit. For example, if in the NINDS clinical trials 50% of the patients received tPA within 90 minutes, and in clinical use a hospital delvers 90% of the doses between 150 and 180 minutes, it would be no surprise if the results of the two would differ. Lastly, how blood pressure is managed may greatly influence outcome, since poorly controlled hypertension may increase the risk of a cerebral hemorrhage following tPA use. It was not specified in the NINDS clinical trials nor in most of the phase IV studies how BP was managed.
  • 44 54 54 In clinical practice, it can often be difficult to select the “right” patient for tPA use. Histories can be unreliable, and assessing the exact time of the stroke onset can be difficult. Also, many of the CTs will have a hypodense area that suggests the presence of either a prior stroke or a current stroke of greater than 180 minutes duration. All practitioners at some point consider not using tPA because we have been taught to “first do no harm”. We wish not to worsen the effects of the ischemic stroke by causing hemorrhagic conversion following a therapy that we provide.
  • 44 54 54 In clinical practice, we must consider tPA use, given its status as the standard of care in acute stroke. Because patient selection can be difficult, we must optimize the potential for benefit and minimize the risk of hemorrhagic conversion. This means finding the patient who is sick enough to benefit from the tPA use, but not so sick that the drug will, in fact, worsen the patient’s outcome. Based on the review of the phase IV studies, it appears that less than 2% of all stroke patients will actually receive tPA. This means that in order for any single Emergency Physician to gain meaningful experience with this drug, he or she must treat a large number of stroke patients in clinical practice.
  • 44 54 54 During a five year period, 13 phase IV studies from both community and academic centers from three countries were published. Up to 389 patients were seen in one of these series, coming from as many as 57 hospitals in one series. Approximately two-thirds of hospitals reporting the data were community (non-academic) hospitals. Up to 22% of eligible patients were treated in one series, which is a reflection of both patient selection for the denominator (total stroke patients seen) and the system for tPA delivery in that institution.
  • 44 54 54 The ages and NIHSS median scores in these phase IV series were comparable to those seen in the NINDS clinical trials. As was suggested previously, at least half of the patients in all of these series received tPA during the third hour following stroke symptom onset.
  • 44 54 54 The most difficult measure to compare between the NINDS trials and the phase IV clinical series is the measure of outcome. This is not surprising, since outcome measurement requires long-term follow-up and unbiased reporting, both of which are difficult in an un-funded, non-blinded phase IV study. As such, there is a wide range of outcomes reported in the phase IV series, but overall general agreement with the results of the NINDS clinical trials. Although ICH and symptomatic ICH rates occurred more frequently in some of the clinical series, the average rates across all of the series were similar to those seen in the NINDS studies. The overall mortality rates in these series also closely approximated the mortality rate seen in the NINDS trials. Even in n the two series with much higher symptomatic ICH rates, the mortality rates in these series were comparable to the mortality rate seen in the NINDS trials.
  • 44 54 54 The most important aspect of the phase IV clinical trials to consider is the rate with which protocol violations occurred in clinical practice. In other words, in clinical practice, were we able to deliver tPA as it was designed to be used in the NINDS efficacy trials? Deviation from the NINDS clinical trials protocol occurred in up to 67% of patients in one phase IV series, with a minimum of 1.3% protocol deviations in the thirteen case series. The two most common errors were the use of tPA beyond the 180 minute window and the concomitant use of other anti-coagulants after tPA use. Other protocol deviations included inadequate BP control, the non-detection of a baseline coagulopathy, an the inability to detect CT findings which might preclude tPA use. It should be noted, however, that the non-detection of edema/mass effect (which suggests a stroke of greater than 180 minutes duration) occurred in the NINDS clinical trials at a comparable rate.
  • 44 54 54 In the Chui study, it was noted that with an increase of five points in the NIHSS score, the likelihood of a favorable outcome decreased by 69%. This means that a patient with an NIHSS score of 24 would have only one-tenth the likelihood of a favorable outcome after tPA use as would a patient with an NIHSS score of 14. This is an important consideration, one this supported by the tPA label information, that suggests in the NINDS study, patients with an NIHSS trended towards having a higher rate of symptomatic ICH within the first 36 hours. The Grond study, from Germany, reported that 22% of eligible patients were treated with tPA. This rate is higher than the rates seen in all of the other phase IV studies of tPA use. Also noteworthy was the treatment of two patients who awoke with stroke symptoms, for whom the exact time of symptom onset was not clearly established. Smith’s report from four affiliated hospitals showed that 70% of patients were treated within the last 30 minutes of the three hour window, and that 19% were treated at times greater than 180 minutes. Although the symptomatic ICH rate was higher than that seen in the NINDS trials, the mortality rate was comparable.
  • 44 54 54 The Tanne study, despite having an organized stroke triage system and experience at delivering tPA, still reported a 30% protocol violation rate, most commonly the co-administration of anticoagulants (15%) and tPA use after 180 minutes (8%). Despite these protocol violations, the ICH and mortality rates were similar to those seen in the NINDS trials. Wang reported tPA in a regional stroke network from Illinois, with results similar to those in the NINDS study. The use of tPA in 6.3% of eligible patients was the largest rate in all of the North American studies. The median time to treatment in this study was 150 minutes, and 9% of patients were treated outside of the three hour window. The Buchan study, from one Canadian teaching hospital, showed a 16% protocol violation rate. These violations included the presence of clinical and CT findings suggesting ineligibility for tPA use. The authors reported that 10 of the 11 protocol violation patients sustained symptomatic ICH, death, or severe disability after tPA therapy, such that adhering to the NINDS protocol is of critical importance.
  • 44 54 54 The STARS study is the largest series published to date, including 389 patients from 57 hospitals. Although there was a 33% protocol violation rate and the median time to therapy was 165 minutes, the results of this phase IV study were similar to those seen in the NINDS trials. In fact, the symptomatic ICH rate was nearly half that seen in the NINDS patients. The Katzan article reports the results of the Cleveland, OH experience. In it, only 70 (1.8%) of 3,948 patients received tPA. The 50% protocol violation rate was seen to decrease over time, suggesting a learning curve with the use of tPA in stroke. The use of anticoagulants in 37%, and the use of tPA outside of three hours in 13% of patients were the two most common problems. Also noted to be problematic were the findings that only 40% of tPA-treated patients had an NIHSS score calculated, and that only 48% had blood pressure management consisten with the NINDS protocol. This study demonstrated a 16% symptomatic ICH rate, but it was not correlated with protocol violations, as was the case in Buchan study.
  • 44 54 54 The German data from Koennecke suggests that some clinicians are willing to give tPA outside of the 180 minute window. Over the two years during which data was collected, the median time to tPA administration only decreased 14%, suggesting that there are rate limiting steps that prevent use much below 60-90 minutes. Over the two years, the number of patients receiving tPA approached 1 per week. The phase IV data from Chapman in Canada reports a 1.8% treatment rate, and a similarly long median treatment time of 165 minutes. Despite the fact that there was a 17% protocol violation rate, the symptomatic ICH rate was quite low, at 2.2%.
  • 44 54 54 The Schmulling data, also from Germany, reported a very low rate of protocol violations, both cases in which the patients had the stroke symptoms upon awakening, such that the exact time of symptom onset was unclear. The 4% mortality rate at three months is the lowest rate reported in any of these studies, perhaps due to having slightly lower NIHSS data than in the other studies (median NIHSS = 11). Grotta’s Houston data reported one of the highest rates of treatment, with 16% of eligible pateints being treated. The highest rate of symptomatic ICH was in patients with a known protocol deviation (15%), as compared to the 4.5% overall rate. The number of symptomatic ICHs decreased over the four year study period. The in-hospital NIHSS declined 79%, from 14 at the time of initial evaluation to 3 at the time of hospital discharge.
  • 44 54 54 The most recent data is published from 10 Connecticut hospitals, only one of which had full neurology and radiology capabilities around the clock. On average, only six patients per year were treated, or one patient every two months. Despite an extremely high rate of protocol violations, the rate of symptomatic hemorrhage was comparable to the rates seen in the NINDS trials and the phase IV studies. This study, did report the highest mortality rate, despite having similar patient demographics.
  • 44 54 54 The are four overall concepts to note from these thirteen studies. First, in most studies, the time to tPA treatment approached the 180 minute window. Second, there are many reports of protocol violations when tPA is used outside of the rigid protocol oversight seen in the NINDS clinical trials. The most commonly observed protocol deviation is the finding of tPA administration at > 180 minutes. Lastly, despite these limitations, the results of tPA use in clinical practice, as reported in the phase IV studies, are comparable to those seen in the NINDS trials.
  • 44 54 54 Only one study specifically examined the issue of age when considering the use of tPA in ischemic stroke, the STARS study published by Albers. In the NINDS trial, two thirds of patients were between 57 and 81 years of age, and the maximum ages in all of the studies ranged from 87 to 100 years of age. It is noteworthy that many of the deaths in elderly patients who received tPA was from AMI, and not necessarily from a complication of the use of tPA such as ICH.
  • 44 54 54 In Albers’ STARS study, patients over the age of 85 were up to 50% less likely to have a good outcome after an ischemic stroke, which included full neurologic recovery or recovery to independent living. Despite this finding, younger patients, those < 65 years of age, were not necessarily more likely to have a good outcome with the use of tPA in stroke, a result that does not support a more aggressive use of the drug in younger patients overall. This observation, however, may have been due to small number, since the odds were improved in this younger age group.
  • 44 54 54 Regarding the issue of age and the use of tPA, it is known that the complication risks are greater, and the likelihood of independent recovery is less with advanced age patients. More information is needed in order to know whether this is due to greater stroke severity in older patients, and whether the complication of significant ICH increases with advanced age.
  • 44 54 54 The CT showed no low density areas suggestive of a stroke of greater than three hours in duration. There was no midline shift or mass effect, and there was no evidence of hemorrhage.
  • 44 54 54 tPA was administered without complication after phone neurologic consultation and after discussing the options with the patient.
  • 44 54 54 tPA was dosed as shown, and the repeat neurological exam at 90 minutes demonstrated an improvement in the apparent NIH stroke scale score.
  • During the hospital course, the patient improved and was dispositioned to a rehabilitation facility, and had some residual deficit at that time.
  • 44 54 54 The NINDS efficacy trials demonstrated improved outcome with tPA use when following a strict clinical protocol. The possible complication of hemorrhagic conversion of the ischemic CNS event does, however, suggest a narrow therapeutic window for tPA use. The nine phase IV reports do suggest that tPA can be used with outcomes similar to that seen in the NINDS clinical trials, provided that the protocol used in that efficacy study are adhered to in clinical practice. Most importantly, clinicians must know the time of symptom onset exactly, must know the treatment guidelines followed in the efficacy trials, and must know how to detect CT abnormalities that would preclude tPA use. Lewandowski has reported the single most useful statistic for the clinician to consider: it is necessary to correctly treat only eight acute stroke patients with tPA in order to be able to successfully return one of these stroke patients to his or her normal baseline prior to the stroke occurrence.
  • 44 54 54 In summary, although it is apparent that tPA is effective in treating acute stroke patients, the therapeutic window is relatively narrow because of the not rare complication of hemorrhagic conversion. Although in clinical practice no single Emergency Physician will use tPA with great regularity, it is still possible to achieve the good outcomes observed in the NINDS efficacy trials. In order to achieve the good results seen in the NINDS study, the practitioner must know how to determine which patients will optimize the risk/benefit ratio using the NIHSS, and must know which patients to exclude, especially if adequate BPO control cannot be achieved. Lastly, because protocol violations have been observed in clinical practice, it is essential to know the NINDS efficacy trials treatment protocol and attempt to reproduce it in order to maximize the outcome of the stroke patients that we treat in the Emergency Department.
  • 1 54 54 Please feel free to contact me or to look up more information on the FERNE website at www.ferne.org.
  • PowerPoint Presentation

    1. 1. Clinical Use of tPA in Acute Ischemic Stroke Edward P. Sloan, MD, MPH Associate Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL
    2. 2. Objectives <ul><li>Present a clinical case history </li></ul><ul><li>Review the NINDS clinical trials </li></ul><ul><li>Examine phase IV tPA clinical data </li></ul><ul><li>Discuss tPA use in ischemic stroke in light of the phase IV clinical data </li></ul>
    3. 3. Clinical History <ul><ul><li>A 62 year old female acutely developed aphasia and right sided weakness while in the grocery store. The store clerk immediately called 911, with the arrival of CFD paramedics within 9 minutes, at 6:43 pm. She arrived at the ED at 7:05 pm, completed her head CT at 7:25 pm, and obtained a neuro consult at 7:35 pm, approximately one hour after the onset of her symptoms. What are the next Rx steps? </li></ul></ul>
    4. 4. ED Presentation <ul><ul><li>On exam, BP 116/63, P 90, RR 16, T 98, and pulse oximetry showed 99% saturation.  The patient appeared alert, and was able to slowly respond to simple commands.  The patient had a patent airway, no carotid bruits, clear lungs, and a regular cardiac rate and rhythm. The pupils were pinpoint, and there was neglect of the R visual field. There was facial weakness of the R mouth, and R upper and lower extremity motor paralysis.  DTRs were 2/2 on the left and 0/2 on the right.  Planter reflex was upgoing on the right and downgoing on the left. The patient’s estimated weight was 50 kg. </li></ul></ul>
    5. 5. Clinical Use of tPA Questions <ul><li>What did the NINDS clinical trials show? </li></ul><ul><li>What are the important design issues of the NINDS clinical trials? </li></ul><ul><li>What documentation is necessary when using tPA in the clinical setting? </li></ul><ul><li>What is the difference between clinical efficacy and effective tPA use? </li></ul>
    6. 6. Clinical Use of tPA Questions <ul><li>What did the phase IV studies show? </li></ul><ul><li>What specific findings from these phase IV studies are most notable? </li></ul><ul><li>What clinical considerations can be derived from these phase IV studies? </li></ul><ul><li>What can be concluded from the NINDS clinical trials and these phase IV studies? </li></ul><ul><li>What issues are relevant when considering the phase IV reports of tPA use? </li></ul>
    7. 7. NINDS Clinical Trials: Main Results <ul><li>tPA within 180 minutes: 30% better outcome at 90 days </li></ul><ul><li>ICH rate at 36 hours 3x greater (10.9 vs. 3.5%) </li></ul><ul><li>Symptomatic ICH rate 10x greater (6.4 vs. 0.6%) </li></ul><ul><li>Mortality at 90 days comparable (17 vs. 21%) </li></ul>
    8. 8. NINDS Clinical trials: Design Issues <ul><li>BP above 185/110 excluded </li></ul><ul><li>“ Aggressive Rx” of BP patients excluded </li></ul><ul><li>All anti-coagulated pts (48 hrs) excluded </li></ul><ul><li>No anti-coag or anti-platelet Rx for 24 hrs </li></ul><ul><li>BP kept “within pre-specified values” </li></ul>
    9. 9. Clinical tPA Use: E.D. Documentation <ul><li>With tPA use, there is a 30% greater chance of a good outcome at three months </li></ul><ul><li>With tPA use, there is 10 fold greater chance of a symptomatic ICH </li></ul><ul><li>Mortality rates at three months are comparable, even though ICH is more common with tPA use </li></ul><ul><li>The rationale for using or not using tPA, given the potential for benefit and the risks of Rx </li></ul>
    10. 10. Clinical Efficacy vs. Effective Clinical Use <ul><li>Efficacy: power or capacity to produce a desired effect </li></ul><ul><li>Effective clinical use: can a drug be used with efficacy outside of the rigors of a clinical trial? </li></ul><ul><li>Can Emergency Physicians on the front line replicate the outcomes seen in the clinical trial? </li></ul><ul><li>Why might outcomes differ in clinical practice? </li></ul>
    11. 11. Clinical Use: Outcome Differences <ul><li>Differences in: </li></ul><ul><ul><li>Patient selection </li></ul></ul><ul><ul><li>Intervention administration </li></ul></ul><ul><ul><li>Concomitant therapy administration </li></ul></ul><ul><ul><li>Outcome measurement </li></ul></ul><ul><ul><li>Expertise of the practitioners in providing this care </li></ul></ul><ul><li>Which of these are the cause (if any) of the differences seen in the phase IV reports? </li></ul>
    12. 12. Clinically Relevant tPA Issues: Stroke Severity <ul><li>NINDS NIHSS Severity: median score = 14 </li></ul><ul><li>NIHSS: 42 point scale, 11 categories </li></ul><ul><li>Mild facial paralysis: NIHSS = 1 </li></ul><ul><li>Complete r hemiplegia with aphasia, gaze deviation, visual field deficit, dysarthria, sensory loss: NIHSS = 25 </li></ul><ul><li>NIHSS severity is critical to pt selection </li></ul>
    13. 13. Clinically Relevant tPA Issues: Clinical Considerations <ul><li>Age </li></ul><ul><li>Size of stroke, based on NIHSS and CT </li></ul><ul><li>% of eligible patients who receive Rx </li></ul><ul><li>Timing of the tPA administration within the 180 minutes (NINDS trials Rx: 48% within 90 minutes) </li></ul><ul><li>How is BP managed? </li></ul>
    14. 14. Clinically Relevant tPA Issues: Clinical Considerations <ul><li>Patient selection is painfully difficult </li></ul><ul><li>Histories are unreliable </li></ul><ul><li>Timing issues hard to press for stroke </li></ul><ul><li>Every CT has a hypodense area </li></ul><ul><li>Tendency not to intervene </li></ul><ul><li>First do no harm </li></ul><ul><li>What we did vs. what was destined to be </li></ul>
    15. 15. NINDS Clinical trials of tPA: Clinical Upshot <ul><li>tPA must be considered </li></ul><ul><li>Patient selection is very difficult </li></ul><ul><li>Must maximize risk/benefit ratio </li></ul><ul><li>Must avoid hemorrhage, if possible </li></ul><ul><li>Need adequate severity, but not too severe </li></ul><ul><li>Less than 2% of patients will meet criteria </li></ul>
    16. 16. Phase IV Reports of tPA Use: An Overview <ul><li>13 publications: Jan 1998 to Sep 2002 </li></ul><ul><li>US 8, Germany 3, Canada 2 </li></ul><ul><li>One to 57 hospitals </li></ul><ul><li>Mix of community and academic centers, 65% community </li></ul><ul><li>37 to 389 patients (312 in NINDS trials) </li></ul><ul><li>Rx of 1.8 to 22% of eligible patients </li></ul>
    17. 17. Phase IV Reports of tPA Use: Patient Selection, Time to Rx <ul><li>Age: 63-71 years old (NINDS = 68 years) </li></ul><ul><li>Median NIHSS: 10-15 (NINDS = 14) </li></ul><ul><li>Median time to Rx: 126 to 165 minutes </li></ul><ul><li>Age and NIHSS comparable </li></ul><ul><li>Time to Rx higher than in NINDS trials </li></ul>
    18. 18. Phase IV Reports of tPA Use: Favorable Outcome, Mortality, ICH <ul><li>Good outcome: 30-95% (NINDS = 31-54%) </li></ul><ul><li>Mortality: 5.3-25% (14%) (NINDS = 17%) </li></ul><ul><li>ICH rate: 9-31% (10%) (NINDS = 11%) </li></ul><ul><li>Sx ICH: 3.3-16% (5.2%) (NINDS = 6.4%) </li></ul><ul><li>Two reports: sx ICH rates o f 11, 16% </li></ul><ul><li>Mortality comparable in these two reports </li></ul><ul><li>Comparable rates overall </li></ul>
    19. 19. Phase IV Reports of tPA Use: Protocol Deviations <ul><li>Deviations occurred in 1.3-67% of patients </li></ul><ul><li>Rx beyond 180 min: 0-22% </li></ul><ul><li>Anti-coagulant use: 2.2-37% </li></ul><ul><li>BP not controlled: 3-7% </li></ul><ul><li>Baseline coagulopathy: 1.5-4% </li></ul><ul><li>CT shows large stroke: 2-6.5% </li></ul><ul><li>CT edema/mass effect: 2-10% (NINDS 3-5%) </li></ul>
    20. 20. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Chiu: Stroke 1998 </li></ul><ul><ul><li>NIHSS 5 points higher, dec good outcome by 69% </li></ul></ul><ul><ul><li>(NIHSS 24 vs. 14, 90% less likely good outcome) </li></ul></ul><ul><li>Grond: Stroke 1998 </li></ul><ul><ul><li>Germany, 22% of eligible pts treated </li></ul></ul><ul><ul><li>Two patients awoke with stroke sx, still Rx’d </li></ul></ul><ul><li>Smith: Acad Emer Med 1999 </li></ul><ul><ul><li>70% Rx’d in last 30 minutes </li></ul></ul><ul><ul><li>19% outside of 180 minute window </li></ul></ul><ul><ul><li>11% Sx ICH rate, but mortality comparable </li></ul></ul>
    21. 21. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Tanne: Neurology 1999 </li></ul><ul><ul><li>Organized stroke triage system and tPA experience </li></ul></ul><ul><ul><li>30% protocol violation rate, comparable outcome </li></ul></ul><ul><li>Wang: Stroke 2000 </li></ul><ul><ul><li>Regional stroke network </li></ul></ul><ul><ul><li>6.3% of eligible pts Rx’d, highest in US </li></ul></ul><ul><ul><li>Median time to Rx: 150 minutes </li></ul></ul><ul><li>Buchan: Neurology 2000 </li></ul><ul><ul><li>Canada, 16% protocol deviation rate </li></ul></ul><ul><ul><li>10/11 (90%) of protocol deviation pts: Sx ICH, mortality, or severe disability </li></ul></ul>
    22. 22. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Albers (STARS study): JAMA 2000 </li></ul><ul><ul><li>Largest series to date (389 patients), prospective </li></ul></ul><ul><ul><li>Median Rx time: 165 minutes </li></ul></ul><ul><ul><li>33% protocol violation rate </li></ul></ul><ul><ul><li>Results similar to NINDS results </li></ul></ul><ul><li>Katzan: JAMA 2000 </li></ul><ul><ul><li>Cleveland: 3,948 pts screened, 1.8% Rx’d </li></ul></ul><ul><ul><li>50% protocol violation rate, less over time </li></ul></ul><ul><ul><li>37% use of anticoagulants, 13% outside of window </li></ul></ul><ul><ul><li>Low measurement of NIHSS, BP control a problem </li></ul></ul>
    23. 23. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Koennecke: Stroke 2000 </li></ul><ul><ul><li>Germany, 75 pts over 2 years, at 144 minutes </li></ul></ul><ul><ul><li>17% treated after three hours, 3% ICH, 15% mortality </li></ul></ul><ul><ul><li>Over 2 yrs, median door-needle 96 to 73 min (14%) </li></ul></ul><ul><ul><li>Patients per month increased 100% (2 to 4 pts) </li></ul></ul><ul><li>Chapman: Stroke 2000 </li></ul><ul><ul><li>Canada, single university hospital </li></ul></ul><ul><ul><li>1.8% of 2,556 pts Rx’d </li></ul></ul><ul><ul><li>Median time to Rx: 165 minutes </li></ul></ul><ul><ul><li>17.4% violations, 2.2% sx ICH </li></ul></ul>
    24. 24. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Schmulling: Stroke 2000 </li></ul><ul><ul><li>150 German pts over 2+ years, academic center </li></ul></ul><ul><ul><li>Protocol deviations in only 1.3% of patients </li></ul></ul><ul><ul><li>Lowest mortality rate: 4% at three months </li></ul></ul><ul><li>Grotta: Arch Neurol 2001 </li></ul><ul><ul><li>Houston, 269 patients, 16% of eligible patients </li></ul></ul><ul><ul><li>In protocol deviation pts, 15% sx ICH rate </li></ul></ul><ul><ul><li>Sx ICH rate declined over the four year period </li></ul></ul><ul><ul><li>Median NIHSS declined 79% (14 to 3) </li></ul></ul>
    25. 25. Phase IV Reports of tPA Use: Notable Specific Findings <ul><li>Bravata: Arch Internal Med 2002 </li></ul><ul><ul><li>2.5 year retrospective look from 10 CT hospitals </li></ul></ul><ul><ul><li>Only one hospital had 24/7 neurology, radiology </li></ul></ul><ul><ul><li>63 pts, 42 (67%) with a protocol violation </li></ul></ul><ul><ul><li>Time > 180 minutes (22%), edema on CT, baseline coagulopathy, and anticoagulants given (all 10%) </li></ul></ul><ul><ul><li>Comparable (6%) sx ICH rate </li></ul></ul><ul><ul><li>Highest in-house mortality rate: 25% </li></ul></ul>
    26. 26. Phase IV Reports of tPA Use: Overall Findings <ul><li>Time to Rx near 180 minute window </li></ul><ul><li>Many reports of protocol violations </li></ul><ul><li>Most common protocol deviation: giving tPA at > 180 minutes </li></ul><ul><li>NINDS population and results can be duplicated </li></ul>
    27. 27. Clinical Use of tPA : The Issue of Age and Outcome <ul><li>Only one study specifically addresses age </li></ul><ul><li>NINDS clinical trial: 69 + 12 years </li></ul><ul><ul><li>66% of patients in age range 57-81 years </li></ul></ul><ul><ul><li>95% of patients in age range 45-93 years </li></ul></ul><ul><li>Maximum ages in studies: 87,90,91, 100 yrs </li></ul><ul><li>Many deaths result from AMI </li></ul><ul><li>Albers, STARS study examined age, outcome </li></ul>
    28. 28. Clinical Use of tPA : Albers’ STARS Study <ul><li>Age > 85 years causes greater risk </li></ul><ul><ul><li>40-50% less likely to have a good outcome </li></ul></ul><ul><ul><li>Neurologic independence or recovery </li></ul></ul><ul><li>Age < 65 not associated with better outcome </li></ul><ul><ul><li>Improved odds, but not statistically significant </li></ul></ul>
    29. 29. Clinical Use of tPA : Conclusions About Age <ul><li>Greater age, greater risk </li></ul><ul><ul><li>Complication risk greater </li></ul></ul><ul><ul><li>Outcome risk less </li></ul></ul><ul><li>Is severity greater in older patients? </li></ul><ul><li>Do ICH occur more often after tPA? </li></ul><ul><li>Is data as good as with tPA use in AMI? </li></ul><ul><li>More information must be provided </li></ul>
    30. 30. Clinical Use of tPA: CT Result in the Clinical Case
    31. 31. Clinical Use of tPA: ED Management of the Clinical Case <ul><li>CT: no low density areas or bleed </li></ul><ul><li>No clear contra-indications to tPA </li></ul><ul><li>NIH stroke scale: approximately 20 </li></ul><ul><li>Neurologist said OK to treat </li></ul><ul><li>No family to defer tPA use </li></ul><ul><li>tPA administered without comp </li></ul>
    32. 32. Clinical Use of tPA: tPA Use & Repeat Exam <ul><li>tPA dosing: </li></ul><ul><ul><li>8:21 pm, approx 1’45” after CVA sx onset </li></ul></ul><ul><ul><li>Initial bolus: 5 mg slow IVP over 2 minutes </li></ul></ul><ul><ul><li>Follow-up infusion: 40 mg infusion over 1 hour </li></ul></ul><ul><li>Repeat exam at 90 minutes: </li></ul><ul><ul><li>Repeat Px Exam: Increased speech & use of R arm, decreased mouth droop & visual neglect </li></ul></ul><ul><ul><li>Repeat NIH stroke scale: approximately 14-16 </li></ul></ul>
    33. 33. Clinical Use of tPA: Hospital Course & Disposition <ul><li>Hospital Course: No hemorrhage, improved neurologic function </li></ul><ul><li>Disposition: Rehab hospital </li></ul><ul><li>Deficit: Near complete use of RUE, speech & vision improved, some residual gait deficit </li></ul>
    34. 34. Clinical Use of tPA : Overall Considerations <ul><li>NINDS clinical trials: Improved outcome </li></ul><ul><li>Narrow therapeutic window important </li></ul><ul><li>Phase IV reports: Effective tPA use possible </li></ul><ul><li>Need to follow NINDS protocol in clinical use </li></ul><ul><li>Need to determine time of sx onset exactly </li></ul><ul><li>Need to know guidelines, know CT findings </li></ul><ul><li>Lewandowski: Eight needed to treat in order to return one pt to full recovery </li></ul>
    35. 35. Clinical Use of tPA : Overall Conclusions <ul><li>tPA is effective, but complications do occur </li></ul><ul><li>Narrow therapeutic window for tPA </li></ul><ul><li>In practice, relatively few pts receive tPA Rx </li></ul><ul><li>Outcomes as in NINDS trials can be achieved </li></ul><ul><li>Knowing the NIHSS is important in pt selection </li></ul><ul><li>A checklist of exclusion criteria is critical </li></ul><ul><li>BP Rx to achieve 185/110 is critical </li></ul><ul><li>Protocol violations occur, know the protocol! </li></ul>
    36. 36. Questions ?? www.ferne.org Edward P. Sloan, MD, MPH [email_address] 312 413 7490