- Email: [email protected]
Treatment With Tissue Plasminogen Activator Is Not Associated With Increased Use of Neurosurgery
Treatment With Tissue Plasminogen Activator Is Not Associated With Increased Use of Neurosurgery Enrique C. Leira,
MD,
Salvador Cruz-Flores, MD, Aninda B. Acharya, Yi Pan, MD, PhD
MD,
and
Background: Current guidelines of stroke care imply that tissue plasminogen activator (rtPA) should be only used in centers with a neurosurgeon available to manage any intracranial hemorrhage (ICH). Such advice may be difficult to follow with the current US shortage of neurosurgeons. It could also contribute to the underutilization of rtPA in smaller hospitals and might not be justified if, in practice, most ICHs were managed medically. Methods: Using the Health Cost Utilization Project 2000 sample we studied the relationship among ischemic stroke, ICH, and rtPA. Results: In this sample of 7,450,992 hospital admissions, 1516 patients had both ischemic stroke and ICH. Among these patients, 58 had received rtPA and 5 of those (8.6%) had a neurosurgical intervention. In the remaining 1458 patients who did not receive rtPA, 178 (12.2%) had neurosurgery. Therefore, the odds ratio for having a neurosurgical intervention for ICH after rtPA was 0.68 (95% confidence interval: 0.27-1.7). Conclusions: In this large sample of US hospital admissions as a result of acute ischemic stroke with overlapping hemorrhage, the use of rtPA was not associated with an increased number of neurosurgical interventions. This lack of association, which needs to be confirmed in prospective studies, argues against withholding treatment with rtPA in patients with stroke based on neurosurgical availability. Key Words: Stroke—thrombolysis— utilization— complications— guidelines. © 2005 by National Stroke Association
The use of intravenous (IV) tissue plasminogen activator (rtPA) for acute stroke is still limited.1 The current guidelines regarding the use of thrombolytics in stroke recommend that in case of hemorrhagic complications “neurosurgical consultation should be obtained in the
From the Souers Stroke Institute, Department of Neurology, Saint Louis University. Received July 21, 2005; accepted August 5, 2005. Supported by local funds from the Souers Stroke Institute, Saint Louis University. Presented in part at the Eighth International Symposium on Thrombolysis and Acute Stroke Therapy in Whistler, British Columbia, Canada, June 20, 2004. Address correspondence to: Enrique C. Leira, MD, Division of Cerebrovascular Diseases, Department of Neurology, 2RCP, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA 52246. E-mail: [email protected]. 1052-3057/$—see front matter © 2005 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2005.08.005
278
event surgical treatment is needed.”2 These same guidelines conclude that, “thrombolytic therapy should not be used unless facilities to handle bleeding complications are readily available.” Despite these concerns, neurosurgical interventions for rtPA-induced hemorrhage may be rare. Early evacuations of hematomas have a high risk of rebleeding,3 and, in practice, most of these hemorrhages may be managed medically. In addition, the current malpractice crisis is limiting the availability of neurosurgical capabilities for small US hospitals.4 Therefore, an excessive apprehension to use rtPA based on the availability of neurosurgical services could worsen the current underutilization of this established therapy. We hypothesized that the number of patients undergoing a neurosurgical intervention presumably to evacuate an intracranial hemorrhage (ICH) after receiving IV rtPA for stroke is not higher than in those patients who did not receive rtPA. The study was previously approved by our institutional review board.
Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 6 (November-December), 2005: pp 278-280
TISSUE PLASMINOGEN ACTIVATOR AND NEUROSURGERY
Table 1. Characteristics of the patients and control subjects
Male, % Mean age, y White, % Income ⬎45,000/y, % Medicare, % Mean length stay, d Mean no. of discharge diagnoses In-hospital mortality, %
Received rtPA (n ⫽ 58)
Did not receive rtPA (n ⫽ 1458)
P
43.1 68.6 72.4 41.4 70.7 9.1
50.1 71 58.2 37.0 69.5 10.9
NS NS NS NS NS NS
9.3 41.4
8.5 23.6
.039 .002
NS, Not significant; rtPA, tissue plasminogen activator.
Material and Methods We conducted a case-control study using the large Nationwide Inpatient Sample 2000 database from the Health Cost and Utilization Project. This database represents a stratified sample of 20% of the US community hospitals and contains discharge data from 7,450,992 patients in 28 states. It includes principal and secondary diagnoses, procedures, and discharge status. More detailed data on the design of the survey and the magnitude of sampling errors associated with the estimates are available in the technical documentation.5 The study population consisted of patients hospitalized with ischemic stroke who also had a diagnosis of ICH. These patients were identified using the abstracted discharge diagnoses International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We identified all the patients in the database who shared a diagnosis of ischemic stroke (ICD-9-CM codes 433, 434, or 436) and ICH (ICD9-CM codes 431 or 432). We considered as cases those patients in the study population who had received rtPA (procedural code 9910), and considered as control subjects those who did not receive rtPA. We chose as the primary outcome variable the percentage of patients who underwent a neurosurgical intervention that would suggest a complication after rtPA, which included the following procedural codes: 01, incision skull and cerebral meninges; 0109, other cranial puncture; 012, craniotomy and craniectomy; 0124, other craniotomy; 0125, other craniectomy; 013, incision of brain and cerebral meninges; 0131, incision of cerebral meninges; 0131, incision of cerebral meninges; 0139, other incision of brain; 0213, ligation of meningeal vessel; 022, ventriculostomy; and 023, extracranial ventricular shunt. Data were exported into software (SAS Institute Inc, Cary, NC) for analysis. We used odds ratios and 95% confidence intervals to determine an association.
279
Results In this database 188,522 patients had a diagnosis of ischemic stroke; 1516 had an additional diagnosis of ICH and constituted the study population. In this study population 58 patients (3.8%) had received IV rtPA and 1458 had not. Table 1 compares the available characteristics of the patients who received rtPA with those who did not. Among those 1516 patients, 183 (12.1%) had a neurosurgical intervention (8.6% of patients and 12.2% of control subjects). Table 2 shows the relationship between receiving rtPA and a neurosurgical intervention. The odds ratio for undergoing a neurosurgical intervention after rtPA was 0.68 (95% confidence interval: 0.27-1.72).
Discussion In this large sample of US hospital admissions, the use of rtPA in patients with stroke was not associated with an increased likelihood of a neurosurgical intervention. Because rtPA is known to increase the risk of ICH in patients with stroke, our findings suggest that most patients with rtPA-induced ICH in the community are being treated conservatively. In view of these results, the concern of having a neurosurgeon available before giving rtPA appears unjustified. This could lead to withholding rtPA unnecessarily from eligible patients with stroke and, therefore, contribute to the current problem of rtPA underutilization in the community. Our study does not intend to downplay the role of neurosurgery in the care of patients with stroke. In fact, we found that neurosurgical procedures were relatively common among those patients with ischemic stroke who also bleed, independently of whether rtPA was used or not. These results agree with the recommendation of creating primary stroke centers with neurosurgical capabilities,6 independently of rtPA use. Interestingly, we found increased in-hospital mortality in the group treated with rtPA. Although rtPA does not increase mortality in clinical trials,7-9 it does increase the chances of dying from an ICH. Because our study population only included those patients with ischemic stroke
Table 2. Relationship between the use of tissue plasminogen activator and a neurosurgical intervention in 1516 patients with both ischemic stroke and intracranial hemorrhage Did not undergo neurosurgery
Underwent neurosurgery
Total
Did not receive rtPA 1280 (84.4%) Received rtPA 53 (3.5%) Total 1333
178 (11.7%) 5 (0.3%) 183
1458 58 1516
rtPA, Tissue plasminogen activator.
E.C. LEIRA ET AL.
280
and associated hemorrhage, this figure may not accurately reflect rtPA-related mortality among all patients with ischemic stroke. In addition, we found a higher number of comorbid diagnoses on discharge in the rtPA group. This suggests a more severe disease burden, which it is known to impact in-hospital mortality.10 We have used a large national sample to answer an important question in acute stroke management. We are aware of the limitations of this study design using administrative data. These limitations include the reliability and validity of the clinical ICD-9-CM diagnoses that were not directly verifiable and may have varied across institutions. Another limitation with this design is the uncertainty about the temporal sequence between the surgical interventions and the administration of rtPA, which can raise concerns about cause and effect. However, because recent operation is considered a contraindication for thrombolysis, it is likely that all the surgical interventions occurred after thrombolysis and not before. Finally, those patients who underwent thrombolysis at outside emergency departments and then transferred to another institution may not have had rtPA coded as a procedure at discharge and, therefore, could have been excluded from this analysis. Despite all these limitations, we believe that these findings are relevant to the organization of stroke services and, therefore, deserve further study through prospective series. In summary, although neurosurgical capabilities are a crucial part of comprehensive stroke centers, physicians in community hospitals should be reassured that the use of rtPA in the initial treatment of patients with acute stroke is appropriate even if surgeons are not immediately available. Acknowledgment: We thank Douglas Luke, PhD, School of Public Health, Saint Louis University, for his statistical support.
References 1. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol 2004;61:346-350. 2. Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Circulation 1996;94:1167-1174. 3. Morgenstern LB, Demchuk AM, Kim DH, et al. Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 2001;56:1294-1299. 4. Ruland S, Gorelick PB, Schneck M, et al. Acute stroke care in Illinois: A statewide assessment of diagnostic and treatment capabilities. Stroke 2002;33:1334-1339. 5. Agency for Healthcare Research and Quality. Overview of the HCUP nationwide inpatient sample (NIS) 2000. Available at: http://www.hcup-us.ahrq.gov/ nisoverview.jsp. Accessed September 13, 2005. 6. Alberts MJ, Hademenos G, Latchaw RE, et al. Recommendations for the establishment of primary stroke centers: Brain attack coalition. JAMA 2000;283:3102-3109. 7. 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;274:10171025. 8. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587. 9. Hacke W, Kaste M, Fieschi C, et al. Randomized doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II): Second European-Australasian acute stroke study investigators. Lancet 1998;352:1245-1251. 10. Johnston JA, Wagner DP, Timmons S, et al. Impact of different measures of comorbid disease on predicted mortality of intensive care unit patients. Med Care 2002; 40:929-940.
MD,
Salvador Cruz-Flores, MD, Aninda B. Acharya, Yi Pan, MD, PhD
MD,
and
Background: Current guidelines of stroke care imply that tissue plasminogen activator (rtPA) should be only used in centers with a neurosurgeon available to manage any intracranial hemorrhage (ICH). Such advice may be difficult to follow with the current US shortage of neurosurgeons. It could also contribute to the underutilization of rtPA in smaller hospitals and might not be justified if, in practice, most ICHs were managed medically. Methods: Using the Health Cost Utilization Project 2000 sample we studied the relationship among ischemic stroke, ICH, and rtPA. Results: In this sample of 7,450,992 hospital admissions, 1516 patients had both ischemic stroke and ICH. Among these patients, 58 had received rtPA and 5 of those (8.6%) had a neurosurgical intervention. In the remaining 1458 patients who did not receive rtPA, 178 (12.2%) had neurosurgery. Therefore, the odds ratio for having a neurosurgical intervention for ICH after rtPA was 0.68 (95% confidence interval: 0.27-1.7). Conclusions: In this large sample of US hospital admissions as a result of acute ischemic stroke with overlapping hemorrhage, the use of rtPA was not associated with an increased number of neurosurgical interventions. This lack of association, which needs to be confirmed in prospective studies, argues against withholding treatment with rtPA in patients with stroke based on neurosurgical availability. Key Words: Stroke—thrombolysis— utilization— complications— guidelines. © 2005 by National Stroke Association
The use of intravenous (IV) tissue plasminogen activator (rtPA) for acute stroke is still limited.1 The current guidelines regarding the use of thrombolytics in stroke recommend that in case of hemorrhagic complications “neurosurgical consultation should be obtained in the
From the Souers Stroke Institute, Department of Neurology, Saint Louis University. Received July 21, 2005; accepted August 5, 2005. Supported by local funds from the Souers Stroke Institute, Saint Louis University. Presented in part at the Eighth International Symposium on Thrombolysis and Acute Stroke Therapy in Whistler, British Columbia, Canada, June 20, 2004. Address correspondence to: Enrique C. Leira, MD, Division of Cerebrovascular Diseases, Department of Neurology, 2RCP, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA 52246. E-mail: [email protected]. 1052-3057/$—see front matter © 2005 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2005.08.005
278
event surgical treatment is needed.”2 These same guidelines conclude that, “thrombolytic therapy should not be used unless facilities to handle bleeding complications are readily available.” Despite these concerns, neurosurgical interventions for rtPA-induced hemorrhage may be rare. Early evacuations of hematomas have a high risk of rebleeding,3 and, in practice, most of these hemorrhages may be managed medically. In addition, the current malpractice crisis is limiting the availability of neurosurgical capabilities for small US hospitals.4 Therefore, an excessive apprehension to use rtPA based on the availability of neurosurgical services could worsen the current underutilization of this established therapy. We hypothesized that the number of patients undergoing a neurosurgical intervention presumably to evacuate an intracranial hemorrhage (ICH) after receiving IV rtPA for stroke is not higher than in those patients who did not receive rtPA. The study was previously approved by our institutional review board.
Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 6 (November-December), 2005: pp 278-280
TISSUE PLASMINOGEN ACTIVATOR AND NEUROSURGERY
Table 1. Characteristics of the patients and control subjects
Male, % Mean age, y White, % Income ⬎45,000/y, % Medicare, % Mean length stay, d Mean no. of discharge diagnoses In-hospital mortality, %
Received rtPA (n ⫽ 58)
Did not receive rtPA (n ⫽ 1458)
P
43.1 68.6 72.4 41.4 70.7 9.1
50.1 71 58.2 37.0 69.5 10.9
NS NS NS NS NS NS
9.3 41.4
8.5 23.6
.039 .002
NS, Not significant; rtPA, tissue plasminogen activator.
Material and Methods We conducted a case-control study using the large Nationwide Inpatient Sample 2000 database from the Health Cost and Utilization Project. This database represents a stratified sample of 20% of the US community hospitals and contains discharge data from 7,450,992 patients in 28 states. It includes principal and secondary diagnoses, procedures, and discharge status. More detailed data on the design of the survey and the magnitude of sampling errors associated with the estimates are available in the technical documentation.5 The study population consisted of patients hospitalized with ischemic stroke who also had a diagnosis of ICH. These patients were identified using the abstracted discharge diagnoses International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We identified all the patients in the database who shared a diagnosis of ischemic stroke (ICD-9-CM codes 433, 434, or 436) and ICH (ICD9-CM codes 431 or 432). We considered as cases those patients in the study population who had received rtPA (procedural code 9910), and considered as control subjects those who did not receive rtPA. We chose as the primary outcome variable the percentage of patients who underwent a neurosurgical intervention that would suggest a complication after rtPA, which included the following procedural codes: 01, incision skull and cerebral meninges; 0109, other cranial puncture; 012, craniotomy and craniectomy; 0124, other craniotomy; 0125, other craniectomy; 013, incision of brain and cerebral meninges; 0131, incision of cerebral meninges; 0131, incision of cerebral meninges; 0139, other incision of brain; 0213, ligation of meningeal vessel; 022, ventriculostomy; and 023, extracranial ventricular shunt. Data were exported into software (SAS Institute Inc, Cary, NC) for analysis. We used odds ratios and 95% confidence intervals to determine an association.
279
Results In this database 188,522 patients had a diagnosis of ischemic stroke; 1516 had an additional diagnosis of ICH and constituted the study population. In this study population 58 patients (3.8%) had received IV rtPA and 1458 had not. Table 1 compares the available characteristics of the patients who received rtPA with those who did not. Among those 1516 patients, 183 (12.1%) had a neurosurgical intervention (8.6% of patients and 12.2% of control subjects). Table 2 shows the relationship between receiving rtPA and a neurosurgical intervention. The odds ratio for undergoing a neurosurgical intervention after rtPA was 0.68 (95% confidence interval: 0.27-1.72).
Discussion In this large sample of US hospital admissions, the use of rtPA in patients with stroke was not associated with an increased likelihood of a neurosurgical intervention. Because rtPA is known to increase the risk of ICH in patients with stroke, our findings suggest that most patients with rtPA-induced ICH in the community are being treated conservatively. In view of these results, the concern of having a neurosurgeon available before giving rtPA appears unjustified. This could lead to withholding rtPA unnecessarily from eligible patients with stroke and, therefore, contribute to the current problem of rtPA underutilization in the community. Our study does not intend to downplay the role of neurosurgery in the care of patients with stroke. In fact, we found that neurosurgical procedures were relatively common among those patients with ischemic stroke who also bleed, independently of whether rtPA was used or not. These results agree with the recommendation of creating primary stroke centers with neurosurgical capabilities,6 independently of rtPA use. Interestingly, we found increased in-hospital mortality in the group treated with rtPA. Although rtPA does not increase mortality in clinical trials,7-9 it does increase the chances of dying from an ICH. Because our study population only included those patients with ischemic stroke
Table 2. Relationship between the use of tissue plasminogen activator and a neurosurgical intervention in 1516 patients with both ischemic stroke and intracranial hemorrhage Did not undergo neurosurgery
Underwent neurosurgery
Total
Did not receive rtPA 1280 (84.4%) Received rtPA 53 (3.5%) Total 1333
178 (11.7%) 5 (0.3%) 183
1458 58 1516
rtPA, Tissue plasminogen activator.
E.C. LEIRA ET AL.
280
and associated hemorrhage, this figure may not accurately reflect rtPA-related mortality among all patients with ischemic stroke. In addition, we found a higher number of comorbid diagnoses on discharge in the rtPA group. This suggests a more severe disease burden, which it is known to impact in-hospital mortality.10 We have used a large national sample to answer an important question in acute stroke management. We are aware of the limitations of this study design using administrative data. These limitations include the reliability and validity of the clinical ICD-9-CM diagnoses that were not directly verifiable and may have varied across institutions. Another limitation with this design is the uncertainty about the temporal sequence between the surgical interventions and the administration of rtPA, which can raise concerns about cause and effect. However, because recent operation is considered a contraindication for thrombolysis, it is likely that all the surgical interventions occurred after thrombolysis and not before. Finally, those patients who underwent thrombolysis at outside emergency departments and then transferred to another institution may not have had rtPA coded as a procedure at discharge and, therefore, could have been excluded from this analysis. Despite all these limitations, we believe that these findings are relevant to the organization of stroke services and, therefore, deserve further study through prospective series. In summary, although neurosurgical capabilities are a crucial part of comprehensive stroke centers, physicians in community hospitals should be reassured that the use of rtPA in the initial treatment of patients with acute stroke is appropriate even if surgeons are not immediately available. Acknowledgment: We thank Douglas Luke, PhD, School of Public Health, Saint Louis University, for his statistical support.
References 1. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol 2004;61:346-350. 2. Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Circulation 1996;94:1167-1174. 3. Morgenstern LB, Demchuk AM, Kim DH, et al. Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 2001;56:1294-1299. 4. Ruland S, Gorelick PB, Schneck M, et al. Acute stroke care in Illinois: A statewide assessment of diagnostic and treatment capabilities. Stroke 2002;33:1334-1339. 5. Agency for Healthcare Research and Quality. Overview of the HCUP nationwide inpatient sample (NIS) 2000. Available at: http://www.hcup-us.ahrq.gov/ nisoverview.jsp. Accessed September 13, 2005. 6. Alberts MJ, Hademenos G, Latchaw RE, et al. Recommendations for the establishment of primary stroke centers: Brain attack coalition. JAMA 2000;283:3102-3109. 7. 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;274:10171025. 8. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587. 9. Hacke W, Kaste M, Fieschi C, et al. Randomized doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II): Second European-Australasian acute stroke study investigators. Lancet 1998;352:1245-1251. 10. Johnston JA, Wagner DP, Timmons S, et al. Impact of different measures of comorbid disease on predicted mortality of intensive care unit patients. Med Care 2002; 40:929-940.