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When should patients with stroke receive thrombolytics?
Thrombolytic therapy should be limited to patients with acute ischemic stroke who meet strict inclusion and exclusion criteria (Table) and who can adhere to strict treatment protocol. Patients treated under these conditions have improved combined mortality and disability outcomes at 1 year when treated with recombinant tissue plasminogen activator (rtPA) (number needed to treat [NNT]=18; 95% confidence interval [CI], 11–56) (strength of recommendation [SOR]: B, meta-analysis of randomized controlled trials with significant heterogeneity).1
Treating patients with rtPA outside the strict protocols definitely increases morbidity and mortality (SOR: A). A recent meta-analysis2 on this topic and the Cochrane review1 of eligible studies found the statistical heterogeneity and lack of precision in the analyses bothersome. These authors believed additional data were needed to more precisely define the circumstances in which thrombolysis could be recommended, if ever, for acute ischemic stroke.
TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA
| Inclusion criteria |
| Patient aged 26–79 years with a diagnosis of ischemic stroke, with consistent, measurable, new neurologic deficit that is not clearing spontaneously and causes impairment |
| Onset of symptoms ≤3 hours |
| Informed consent obtained from patient, appropriate family member, or power of attorney |
| Neuroradiologist and neurosurgeon on hand |
| Stroke unit or equivalent team/bed available |
| Exclusion criteria |
| Major neurological deficits |
| Onset of symptoms >3 hours before starting treatment |
| Head trauma or myocardial infarction in previous 3 months |
| Gastrointestinal or urinary tract hemorrhage in previous 21 days |
| Major surgery in previous 14 days |
| Arterial puncture at a noncompressible site in previous 7 days |
| History of intracranial hemorrhage |
| Blood pressure >185 mm Hg systolic or >110 diastolic at time thrombolytic therapy is given INR >1.5 |
| On heparin, or aPTT outside normal range |
| Platelet count <100K mm3 |
| Blood glucose <50 mg/dL (2.7 mmol/L) |
| Seizure with postictal neurological impairments |
| Radiologic evidence that more than one third of cerebral hemisphere (by volume) is involved |
| Inability to maintain adherence to treatment guidelines (Current aspirin use is not an exclusion criterion.) |
| INR, international normalized ratio; aPTT, actived partial thromboplastin time |
Evidence summary
The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”3 The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,4 ECASS,5 and ATLANTIS6 —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.
The NINDS study, often employed as a benchmark,3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”4 Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.
Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,9 a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,10 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.11
Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).1 These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.
The net positive outcome found in the Cochrane review1 results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).1 The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.
Recommendations from others
Recommendations from the American Heart Association,2 the American Academy of Neurology,6 and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy7 substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.
Respect the accepted inclusion and exclusion criteria for using thrombolytics
John Richmond, MD
University of Texas Southwestern Family Practice Residency Program, Dallas
Acute ischemic stroke has always posed the dilemma of giving treatment that may be either beneficial or harmful. Now the stakes of success or failure are dramatically higher. Family physicians must be knowledgeable about treatment options, as the 3-hour window for using rtPA after symptom onset is a diagnostic and logistic challenge for physicians and staff.
Our radiology colleagues help by using the unenhanced head CT to exclude lesions that mimic ischemic infarct and to confirm that true stroke victims do not have identifiable infarction greater than one third of the middle cerebral artery territory. Clinicians involved in the rtPA decision must know and respect fully and without deviation the accepted inclusion and exclusion criteria for using thrombolytics for acute ischemic stroke, to promote recovery and minimize death and disability due to intracranial hemorrhage.
1. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Chichester, UK: John Wiley; 2003.
2. Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke 2003;34:1437-1442.
3. Adams HP, Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Heart Association. Stroke 2003;34:1056-1083.
4. Tissue plasminogen activator for acute ischaemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.
5. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025.
6. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999;282:2019-2026.
7. Practice advisory: thrombolytic therapy for acute ischemic stroke—summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:835-839.
8. Hirsh J, Dalen J, Guyatt G. American College of Chest Physicians. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 2001;119(1 Suppl):1S-2S.
9. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162:1994-2001.
10. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283:1151-1158.
11. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM. Cleveland Clinic Health System Stroke Quality Improvement Team. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34:799-800.
Thrombolytic therapy should be limited to patients with acute ischemic stroke who meet strict inclusion and exclusion criteria (Table) and who can adhere to strict treatment protocol. Patients treated under these conditions have improved combined mortality and disability outcomes at 1 year when treated with recombinant tissue plasminogen activator (rtPA) (number needed to treat [NNT]=18; 95% confidence interval [CI], 11–56) (strength of recommendation [SOR]: B, meta-analysis of randomized controlled trials with significant heterogeneity).1
Treating patients with rtPA outside the strict protocols definitely increases morbidity and mortality (SOR: A). A recent meta-analysis2 on this topic and the Cochrane review1 of eligible studies found the statistical heterogeneity and lack of precision in the analyses bothersome. These authors believed additional data were needed to more precisely define the circumstances in which thrombolysis could be recommended, if ever, for acute ischemic stroke.
TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA
| Inclusion criteria |
| Patient aged 26–79 years with a diagnosis of ischemic stroke, with consistent, measurable, new neurologic deficit that is not clearing spontaneously and causes impairment |
| Onset of symptoms ≤3 hours |
| Informed consent obtained from patient, appropriate family member, or power of attorney |
| Neuroradiologist and neurosurgeon on hand |
| Stroke unit or equivalent team/bed available |
| Exclusion criteria |
| Major neurological deficits |
| Onset of symptoms >3 hours before starting treatment |
| Head trauma or myocardial infarction in previous 3 months |
| Gastrointestinal or urinary tract hemorrhage in previous 21 days |
| Major surgery in previous 14 days |
| Arterial puncture at a noncompressible site in previous 7 days |
| History of intracranial hemorrhage |
| Blood pressure >185 mm Hg systolic or >110 diastolic at time thrombolytic therapy is given INR >1.5 |
| On heparin, or aPTT outside normal range |
| Platelet count <100K mm3 |
| Blood glucose <50 mg/dL (2.7 mmol/L) |
| Seizure with postictal neurological impairments |
| Radiologic evidence that more than one third of cerebral hemisphere (by volume) is involved |
| Inability to maintain adherence to treatment guidelines (Current aspirin use is not an exclusion criterion.) |
| INR, international normalized ratio; aPTT, actived partial thromboplastin time |
Evidence summary
The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”3 The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,4 ECASS,5 and ATLANTIS6 —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.
The NINDS study, often employed as a benchmark,3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”4 Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.
Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,9 a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,10 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.11
Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).1 These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.
The net positive outcome found in the Cochrane review1 results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).1 The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.
Recommendations from others
Recommendations from the American Heart Association,2 the American Academy of Neurology,6 and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy7 substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.
Respect the accepted inclusion and exclusion criteria for using thrombolytics
John Richmond, MD
University of Texas Southwestern Family Practice Residency Program, Dallas
Acute ischemic stroke has always posed the dilemma of giving treatment that may be either beneficial or harmful. Now the stakes of success or failure are dramatically higher. Family physicians must be knowledgeable about treatment options, as the 3-hour window for using rtPA after symptom onset is a diagnostic and logistic challenge for physicians and staff.
Our radiology colleagues help by using the unenhanced head CT to exclude lesions that mimic ischemic infarct and to confirm that true stroke victims do not have identifiable infarction greater than one third of the middle cerebral artery territory. Clinicians involved in the rtPA decision must know and respect fully and without deviation the accepted inclusion and exclusion criteria for using thrombolytics for acute ischemic stroke, to promote recovery and minimize death and disability due to intracranial hemorrhage.
Thrombolytic therapy should be limited to patients with acute ischemic stroke who meet strict inclusion and exclusion criteria (Table) and who can adhere to strict treatment protocol. Patients treated under these conditions have improved combined mortality and disability outcomes at 1 year when treated with recombinant tissue plasminogen activator (rtPA) (number needed to treat [NNT]=18; 95% confidence interval [CI], 11–56) (strength of recommendation [SOR]: B, meta-analysis of randomized controlled trials with significant heterogeneity).1
Treating patients with rtPA outside the strict protocols definitely increases morbidity and mortality (SOR: A). A recent meta-analysis2 on this topic and the Cochrane review1 of eligible studies found the statistical heterogeneity and lack of precision in the analyses bothersome. These authors believed additional data were needed to more precisely define the circumstances in which thrombolysis could be recommended, if ever, for acute ischemic stroke.
TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA
| Inclusion criteria |
| Patient aged 26–79 years with a diagnosis of ischemic stroke, with consistent, measurable, new neurologic deficit that is not clearing spontaneously and causes impairment |
| Onset of symptoms ≤3 hours |
| Informed consent obtained from patient, appropriate family member, or power of attorney |
| Neuroradiologist and neurosurgeon on hand |
| Stroke unit or equivalent team/bed available |
| Exclusion criteria |
| Major neurological deficits |
| Onset of symptoms >3 hours before starting treatment |
| Head trauma or myocardial infarction in previous 3 months |
| Gastrointestinal or urinary tract hemorrhage in previous 21 days |
| Major surgery in previous 14 days |
| Arterial puncture at a noncompressible site in previous 7 days |
| History of intracranial hemorrhage |
| Blood pressure >185 mm Hg systolic or >110 diastolic at time thrombolytic therapy is given INR >1.5 |
| On heparin, or aPTT outside normal range |
| Platelet count <100K mm3 |
| Blood glucose <50 mg/dL (2.7 mmol/L) |
| Seizure with postictal neurological impairments |
| Radiologic evidence that more than one third of cerebral hemisphere (by volume) is involved |
| Inability to maintain adherence to treatment guidelines (Current aspirin use is not an exclusion criterion.) |
| INR, international normalized ratio; aPTT, actived partial thromboplastin time |
Evidence summary
The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”3 The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,4 ECASS,5 and ATLANTIS6 —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.
The NINDS study, often employed as a benchmark,3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”4 Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.
Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,9 a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,10 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.11
Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).1 These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.
The net positive outcome found in the Cochrane review1 results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).1 The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.
Recommendations from others
Recommendations from the American Heart Association,2 the American Academy of Neurology,6 and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy7 substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.
Respect the accepted inclusion and exclusion criteria for using thrombolytics
John Richmond, MD
University of Texas Southwestern Family Practice Residency Program, Dallas
Acute ischemic stroke has always posed the dilemma of giving treatment that may be either beneficial or harmful. Now the stakes of success or failure are dramatically higher. Family physicians must be knowledgeable about treatment options, as the 3-hour window for using rtPA after symptom onset is a diagnostic and logistic challenge for physicians and staff.
Our radiology colleagues help by using the unenhanced head CT to exclude lesions that mimic ischemic infarct and to confirm that true stroke victims do not have identifiable infarction greater than one third of the middle cerebral artery territory. Clinicians involved in the rtPA decision must know and respect fully and without deviation the accepted inclusion and exclusion criteria for using thrombolytics for acute ischemic stroke, to promote recovery and minimize death and disability due to intracranial hemorrhage.
1. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Chichester, UK: John Wiley; 2003.
2. Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke 2003;34:1437-1442.
3. Adams HP, Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Heart Association. Stroke 2003;34:1056-1083.
4. Tissue plasminogen activator for acute ischaemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.
5. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025.
6. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999;282:2019-2026.
7. Practice advisory: thrombolytic therapy for acute ischemic stroke—summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:835-839.
8. Hirsh J, Dalen J, Guyatt G. American College of Chest Physicians. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 2001;119(1 Suppl):1S-2S.
9. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162:1994-2001.
10. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283:1151-1158.
11. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM. Cleveland Clinic Health System Stroke Quality Improvement Team. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34:799-800.
1. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Chichester, UK: John Wiley; 2003.
2. Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke 2003;34:1437-1442.
3. Adams HP, Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Heart Association. Stroke 2003;34:1056-1083.
4. Tissue plasminogen activator for acute ischaemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.
5. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-1025.
6. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999;282:2019-2026.
7. Practice advisory: thrombolytic therapy for acute ischemic stroke—summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:835-839.
8. Hirsh J, Dalen J, Guyatt G. American College of Chest Physicians. The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 2001;119(1 Suppl):1S-2S.
9. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162:1994-2001.
10. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283:1151-1158.
11. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM. Cleveland Clinic Health System Stroke Quality Improvement Team. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003;34:799-800.
Evidence-based answers from the Family Physicians Inquiries Network