EFFECT OF OLDER AGE ON THE RISK OF HEMORRHAGIC COMPLICATIONS AFTER INTRAVENOUS AND/OR INTRA-ARTERIAL THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE

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1 EFFECT OF OLDER AGE ON THE RISK OF HEMORRHAGIC COMPLICATIONS AFTER INTRAVENOUS AND/OR INTRA-ARTERIAL THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE By SVETLANA PUNDIK, M.D. Submitted in partial fulfillment of the requirements for the degree of Masters of Science Clinical Research Scholars Program CASE WESTERN RESERVE UNIVERSITY May 2008

2 Table of Contents Abstract 5 Background and Significance.. 6 Stroke Epidemiology.. 6 What is Ischemic Stroke.6 Stroke Outcome..7 Stroke Treatments and Treatment complications..7 Hypotheses Methods...10 Subjects Clinical data and variable evaluation Thrombolysis treatment protocol...12 Outcome measures 13 Statistical Analysis Results...14 Demographics Population characteristics Symptomatic ICH Asymptomatic ICH Rate of recanalization Discussion References. 33 3

3 List of Tables Table 1. Analysis of linearity of serum glucose variable in the multivariate logistic regression model where outcome variable is SICH and predictors are patient s age, mean arterial pressure, IV route of thrombolytic administration and glucose quartiles.12 Table 2. Analysis of linearity of mean arterial pressure variable in the multivariate logistic regression model where outcome variable is SICH and predictors are patient s age, glucose, IV route of thrombolytic administration and mean arterial pressure quartiles..12 Table 3. Demographic and baseline characteristics of patients treated for acute ischemic stroke..15 Table 4. Characteristics of patients who received IV thrombolysis alone vs. those treated with either IA alone or combination of IV/IA 18 Table 5. Patient characteristics for those with and without the symptomatic intracranial hemorrhage (SICH). 20 Table 6. Logistic regression models for risk of SICH...21 Table 7. Characteristics of patients with asymptomatic intracranial hemorrhage (AICH) or without ICH.. 22 Table 8. Logistic regression models for risks of asymptomatic ICH after thrombolytic therapy 23 Table 9. AICH in different age groups following either IV or IV+-IA thrombolysis...24 Table 10. Characteristics of patients who were observed to have recanalization vs. those that did not recanalized

4 Table 11. Logistic regression models for risks of ICH after thrombolytic therapy for patients 80 years of age or older.. 26 Table 12. Symptomatic intracranial hemorrhage and mortality in the elderly after IV or IA thrombolysis for acute ischemic stroke, literature summary..28 Acknowledgements My sincere thanks for advice, guidance, collaboration and support in conducting this study to: Dr. Jose Suarez Dr. Robert Ruff Dr. Regis McFadden Dr. Rhoderick Machekano Dr. Les Kirchner Dr. Dennis Landis Dr. Laurie McWilliams Dr. Kristine Blackham Dr. Robert Tarr Dr. Jeffrey Sunshine Dr. Sophia Sundararajun Dr. Warren Selman And to my supporting family, David and Daniel Lust 5

5 Older Age does not Increase Risk of Hemorrhagic Complications after Intravenous and/or Intra-arterial Thrombolysis for Acute Stroke Abstract by SVETLANA PUNDIK, M.D. Background: The elderly have significantly higher incidence of ischemic stroke and suffer higher mortality and morbidity compared to younger patients. Intracranial hemorrhage following thrombolysis is one of the causes of unfavorable outcome. Methods: A database of 488 consecutive ischemic stroke patients who received thrombolytic therapy was analyzed using logistic regression model the factors associated with symptomatic intracranial hemorrhage (SICH). Results: The odds of SICH for patients over 80 after adjusting for route of administration, National Institutes of Health Stroke Score, mean arterial pressure and glucose was not significantly different from the younger age group (OR=1.64; 95%CI: ). However, age as a continuous variable was a significant predictor (OR=1.03; 95%CI: ). Hyperglycemia and high blood pressure were associated with increased odds of SICH. Conclusions: Patients over 80 dsis not have higher frequency of SICH. Although, a larger study is indicated, decision to provide thrombolysis should not be based solely on age. 6

6 Background Stroke epidemiology Stroke is the third leading cause of death and the primary cause of disability in the United States. The annual incidence of stroke in general population is 750,000. Stroke is more common in the elderly and the rates of morbidity and mortality following it are higher with increasing age. The incidence of stroke doubles with each consecutive decade above 55 years of age and mortality for patients over 85 is tripled compared to a younger group (1;2). Due to increasing human longevity and growing aging population, stroke will remain a major medial problem in upcoming years. As size of the high-risk stroke population increases so does the cost to care for patients who suffered this life changing disease. It is estimated the care for stroke victims is costing American society about $30 billion per year. A per-patient cost considering expensive long-term care and in most cases loss of productivity is on average $150,000. Therefore, optimization of current therapies trough a careful study of already existing data and development of new treatments with new clinical trials are vitally important tasks for our society. What is Ischemic Stroke In majority of the cases, stroke occurs when the blood flow to a portion of the brain is interrupted by a blood clot. This event usually results in devastating life consequences related to the loss of various functions, including language, movement, sensation, vision and many other. In order to reverse or to minimize the deficits produced by stroke, blood flow to the affected brain region needs to be restored within a limited period of time window. Stroke is a disease that can change person s life instantaneously and failure of blood flow restoration is likely to cause severe disability or death. 7

7 Stroke outcome Outcome after stroke in large part depend on stroke severity, presence of co-existing medical problems such as diabetes mellitus, ability to restore blood flow within first few hours, appropriate management of systemic blood pressure, prevention of complications such as hemorrhagic transformation into the ischemic area and patient s age. As indicated above, the rates of a favorable outcome following stroke are significantly lower in older patients (1;3). Historically clinical trials of acute stroke treatments restricted enrollment of patients over years of age. Due to the exclusion of this population of patients, the information on outcome of the elderly patients managed with modern stroke treatment protocols is limited to observational prospective and retrospective studies. However, not all treatment modalities have been carefully described in older patients. Stoke Treatments and Treatment Complications For over more than a decade physicians in the United States and world wide have been able to help some patients to restore blood flow to the brain using medications that breaks up the blood clot, i.e. urokinase and tissue plasminogen activator (tpa). The procedure is called thrombolysis or thrombolytic therapy. The medication can be administered intravenously or directly into the clot, i.e. intra-arterially. A multidisciplinary team of physicians and support personnel, called the Brain Attack Team, has been formed to treat patients with acute stroke. Care for patient with acute ischemic stroke is a challenging task for even a tertiary care facility. In order to be able to evaluate, diagnose and administer treatment within a very limited amount of time a standby system of multiple medical services has to be available at any time of day or night. A smooth and timely performance of such system is directly related 8

8 to success of patient recovery. Certain steps are mandatory such as ruling out hemorrhage, screening for coagulopathy and management of hypertension prior to administering thrombolytic therapy. However, in spite of significant interventional advances and efforts on the part of physicians taking care of acute stroke patients many patients fail to respond to currently available therapies and in some cases suffer complications related to the treatment, such as brain hemorrhage. The cause of the difficulties accounted in treatment of stroke patients is multifactorial and currently being studied at many different levels. One of the possibilities that could explain the treatment failure is patient s age. The incidence of stroke is predominantly in the adult population greater than 50 years of age. Previous epidemiological studies demonstrated that the older population of patients with stroke experience worse outcomes (4). The cause of this age-related association is not quite clear yet. Aging brain tissue has a reduced tolerance to interruption of blood flow (5;6). The cause of this phenomenon most likely occurs at different levels: physiological, cellular, molecular, and genetic. It is also possible that older patients simply do not respond to thrombolytic therapy as well as younger patients and therefore, fewer of older patients achieve restoration of the blood to the brain. In other words, lack of restoration of blood flow will have the most direct affect on poor outcomes. To my knowledge previous studies have not addressed the question whether older patients have similar rates of recanalization following the thrombolitic therapy as the younger group. One of the factors associated with unfavorable outcome after stroke is symptomatic intracranial hemorrhage (SICH). The risk factors for SICH have been well described. Among them are higher admission blood pressures, higher National Institutes of Health Stroke Score 9

9 (NIHSS), treatment delay, hyperglycemia, history of atrial fibrillation or other cardiac disease and lack of or partial recanalization (7-9). It has been less clear whether advanced age increases the likelihood of intracerebral hemorrhage after thrombolytic treatment of stroke. The NINDS tpa study did not find a correlation between hemorrhage and age, although only 7% of the patients were over the age of 80. More recently, several groups of investigators have found that advanced age (>=80) is not necessarily associated with increased risk for hemorrhage after thrombolysis when treatment is provided by intravenous routes in the first three hours after clinical onset (10-12). There is less published experience related to risks of hemorrhage in elderly individuals who undergo intra-arterial therapy, especially when it is provided more than three hours after clinical onset (13). There was no clear correlation between age and risk for hemorrhage found in PROACT II (14). Kim and colleagues, summarizing experience with intra-arterial therapy over a decade, similarly have found no increased risk of symptomatic hemorrhage (13). Here, we present a review of our experience with thrombolytic therapy for elderly patients. 10

10 Hypotheses Hypothesis I. The risk of symptomatic intracranial hemorrhage following a combination of intravenous and/or intraarterial thrombolysis for acute ischemic stroke for patients who are 80 years of age or older is similar to that of a younger group. Hypothesis II. The rates of recanalization following thrombolysis are similar for patients who are older than 80 years and those who are younger than 80. Methods Subjects We selected patients from the Brain Attack Database at University Hospitals of Cleveland. This database was prospectively collected between October 1993 and May 2006 and contained information on evaluation and treatment of all patients with symptoms suggestive of acute stroke. Written informed consent for data collection was obtained from patients or from their next of kin at the time of initial interview. The database contains information on all the patients for whom urgent evaluation from a Brain Attack team was requested by emergency department or other medical personnel. Only a portion of those evaluated were diagnosed with presumed acute ischemic stroke and were qualified to receive thrombolytic therapy. For hypothesis analysis we selected only patients that received thrombolytic therapy with intravenous and/or intraarterial administration of urokinase (UK) and/or rt-pa. 11

11 Clinical data and variable evaluation The data collected for each subject contained information on demographics, past medical history, severity of the neurological deficits, brain imaging, blood pressure, admission serum glucose and timing of the thrombolysis. Analysis of linearity of the continuous variables was performed. Several continuous variables were dichotomized based on this analysis. Tables 1 and 2 describe the analysis of these variables on the quartile basis. Serum glucose is frequently dichotomized in the published observational reports. We chose to dichotomize serum glucose over 150 mg/dl as was previously done for the analysis of this database and in other reports (15). Route of administration was grouped into Intravenous route (IV) vs. either Intraarterial alone (IA) or IV and IA combination (IV/IA). The rationale of this grouping is based on the premise of this study to investigate whether the IA thrombolytic therapy which is usually reserved for younger patients is safe in the elderly group. Historically patients over age of 80 have been excluded from randomized control studies investigating therapeutic interventions for acute ischemic stroke (16). Therefore, it was chosen to dichotomize age over 80 to determine whether octogenarians have increased risk of intracranial hemorrhage and whether they have a different rate of recanalization following thrombolytic therapy. 12

12 Table 1. Analysis of linearity of serum glucose variable in the multivariate logistic regression model where outcome variable is SICH and predictors are patient s age, mean arterial pressure, IV route of thrombolytic administration and glucose quartiles. Quartile Glucose category 80.5 (59-102) 112 ( ) ( ) ( ) midpoint Estimated Coefficients Frequency Proportion Table 2. Analysis of linearity of mean arterial pressure variable in the multivariate logistic regression model where outcome variable is SICH and predictors are patient s age, glucose, IV route of thrombolytic administration and mean arterial pressure quartiles. Quartile Mean arterial pressure category midpoint Estimated 74 (53-95) (95-107) ( ) ( ) Coefficients Frequency Proportion Thrombolysis treatment protocol Our treatment protocol has been previously published (17-19) but we will summarize it here. Patients that presented within 6 hours from the time of onset of new neurological deficits were evaluated with a non-contrasted head CT. Serum glucose level, complete blood count, and coagulation profile were determined. Thrombolysis was initiated if standard safety 13

13 guidelines parameters (17) were met. Thrombolytics were administered intravenously (IV) only, intraarterialy (IA) only or as a combination of both IV/IA. If patients presented within 3 hours from onset they received either IV or IV immediately followed by IA thrombolysis. Those presenting between 3 and 6 hours received IA thrombolysis only. After May 1999 thrombolytic therapy was limited to rt-pa at doses of 0.9 mg/kg (90 mg max) for IV only administration and 0.6 mg/kg IV/ 0.3 mg/kg IA for a combination protocol. IA only dose was 0.3 mg/kg (22 mg max). Outcome measures Presence of symptomatic or asymptomatic intracranial hemorrhage (ICH) was based on non-contrasted head CT performed for all patients according to our protocol at 24 hours after patients treatment (17-19). Patients were considered to have symptomatic ICH (SICH) if in addition to characteristic CT changes they had a neurological decline defined as an increase of 4 points in the NIHSS. Only parenchymal hematomas were considered to be significant CT changes that could be contributing to neurological worsening (20). Asymptomatic ICH (AICH) was defined as presence of hemorrhage on CT without neurological deterioration. Presence of recanalization, whether complete or partial, was determined only for patients that were evaluated with cerebral angiogram that was performed for diagnostic and therapeutic purposes within the 6 hours from the onset. As a result information on recanalization is available only for a portion of study sample. Board-certified neuroradiologists interpreted all the imaging studies. Board-certified and NIHSS-certified neurologists performed all the NIHSS and subsequent patient care evaluations. 14

14 Statistical analysis Logistic regression analysis was performed using SAS statistical software (v.9.1; SAS Institute Inc., Cary, NC, USA) to determine an association between outcome variables with predictors of interest. Predictor selection for logistic model was based on univariate analysis and only those variables that had an unadjusted effect with p<0.15 were included in the main effect model. Clinically significant variable, age, was retained in the model regardless its influence on the outcome in the univariate analysis. Both continuous and dichotomized age were evaluated. Univariate analysis was performed using t test, Wilcoxon rank sum test and Pearson s χ 2 test, as appropriate. Logistic regression models were evaluated for validity of linearity assumptions and appropriate transformation of continuous variables were performed when assumptions were not met. Investigation of interactions and goodness of fit analysis using the Hosmer-Lemeshow procedure were applied. Null hypothesis was rejected at alpha level < Results Demographics The database contained 1928 cases. The database contains all the patients who were evaluated for eligibility for thrombolytic therapy, but only portion of them qualified. We analyzed data from 488 patients who were treated with thrombolytic therapy for acute ischemic stroke. Patient population characteristics are summarized in Table 3. There were significantly more women in the older cohort of patients, which could be due to increased prevalence of acute ischemic stroke in older women. Older patients were more likely to have a diagnosis of hypertension and less likely to smoke. There was also a greater percent of younger patients that received urokinase. 15

15 Table 3. Demographic and baseline characteristics of patients treated for acute ischemic stroke Variable Age <80 (n=404) Age, mean (SD) in years 62.7 (11.8) range: Age 80 (n=78) 83.3 (3.7) range: P Female 171 (43%) 42 (55%) 0.05 Caucasian 276 (73%) 56 (84%) 0.06 Route: IV 210 (53%) 33 (43%) 0.09 IA or both 183 (47%) 44 (57%) Agent: tpa 274 (70%) 64 (85%) UK or both 108 (28%) 6 (8%) NIHSS, mean (SD) 13 (8) 14 (8) 0.3 MAP, mean (SD) 107 (19) 112 (18) Glucose, mean (SD) 142 (63) 141 (81) 0.5 Onset to treatment in minutes, 198 (101) 181 (81) 0.2 mean (SD) History of Smoking 89 (22%) 6 (8%) Hypertension 251 (61%) 62 (80%) Diabetes 86 (21%) 19 (24%)

16 Stroke 86 (21%) 18 (23%) 0.7 TIA 36 (9%) 9 (11%) 0.4 ICH Symptomatic 42 (10.34%) 10 (12.82%) 0.5 IV only 4.92% 9.09% 0.3 IA or both 15.24% 18.18% 0.7 Asymptomatic 76 (18.81%) 10 (12.82%) 0.2 Recanalization 181 (77%) [235]* * [# of cases available for analysis of recanalization] 26 (72%) [36]* 0.5 Population characteristics Based on the analysis of all selected cases, patients with NIHSS > 18 on admission were more likely to receive IV/IA or IA than IV only therapy, 71% vs. 29% respectively (p<0.0001). Mean NIHSS was 11 (median: 9, range: 1-42) in IV only group and 16 (median: 15, range: 1-42) in IV/IA or IA alone group (p<0.0001). IV/IA and IA cohort also had significantly higher baseline glucose level than IV alone group (149 mg/dl vs. 133 mg/dl, p=0.005). Table 4 represents how patients that were treated with either IV vs. IA plus/minus IV differed in risk factors for SICH. NIHSS on admission for 80 and older patients with and without SICH were not different (median NIHSS: 14 with SICH vs. 13 without SICH, p=0.8). The younger cohort, on the other hand, demonstrated a statistically significant difference in initial NIHSS between 17

17 those with and without SICH (median NIHSS: 19 with SICH and 12 without SICH, p<0.0001). IV only administration was initiated on average by 2.6 hours for both age groups (Table 4). Mean time of treatment initiation for IV/IA or IA only therapy was 3.8 (median: 3.75, range: hours) and 3.6 (median: 2.9, range: hours) hours for younger and older cohorts, respectively. Table 4 describes the group of patients who received IV therapy only and the group that was treated with either IA or IV/IA combination. Important to note that information on recanalization for IV only group is limited for those patients who had angiography but were either discovered to have no occlusion or to have untreatable by thrombolysis disease. Therefore, information on recanalization in IV only group does not represent the true rate of recanalization. The time from onset to treatment was delayed in the group with SICH (Table 5). Time from onset of symptoms to treatment did not differ among elderly with and without SICH (mean: 2.7 hours for patients with hemorrhage and 3 hours for those without, p=0.3). However, in the younger cohort delay of treatment was associated with higher SICH, mean of 3.2 hours for patients without hemorrhage and 3.9 hours for patients with hemorrhage (p=0.005). The rates of SICH after thrombolysis with urokinase vs. tpa were not different in two age cohorts (data not shown). The rates of SICH after tpa alone was 10% in the whole population. 18

18 Table 4. Characteristics of patients who received IV thrombolysis alone vs. those treated with either IA alone or combination of IV/IA Variable IV alone IA or IV/IA P (n=232) (n=244) Age, mean (SD) in years (15.06) (12.75) 0.5 Female gender N(%) 98 (43) 111 (46) 0.5 Caucasian, N(%) 159 (74) 166 (74) 1 NIHSS, mean (SD; range) 11 (9; 1-42) 16 (15; 1-42) < MAP, mean (SD) (19.3) (18.1) 0.72 Glucose, mean (SD) 133 (52.64) 149 (69.15) Onset to treatment in hours, mean (SD) Age< (3.75; ) < Age (2.9; ) SICH, N(%) 13 (5.6) 38 (15.57) Recanalized, N(%) 24 (80) [30]* * [# of cases available for analysis of recanalization] 176 (75) [232]*

19 Symptomatic ICH The main goal of this study was to determine whether patients over 80 suffer greater rates of hemorrhagic consequences following thrombolysis. Therefore, we used logistic regression to analyze whether dichotomized age groups under and over age 80 have different risks of SICH. Table 3 describes the characteristics of the two age groups. Furthermore, we performed logistic regression analysis with age as a continuous variable. In the grouped age analysis, the rates of SICH were 12.82% and 10.4% in older and younger groups, respectively. These rates reflect all routes of administration. However, we found that the hemorrhage rates in the whole cohort was 5.6% following IV only therapy and 15.6% after IV/IA or IA thrombolysis. Logistic regression analysis (Table 6) showed that the risk of SICH following thrombolytic therapy for patients 80 years of age or older after adjusting for route of administration, mean arterial pressure, glucose level, NIHSS on admission, and history of hypertension, was not significantly different from the younger age group. However, logistic regression analysis using age as a continuous variable indicates that 10 year increments in age increase the risk of SICH by 30 %. Hyperglycemia (>150 mg/dl) was associated with increased risk of SICH in both models. Patients with initial mean arterial pressure greater than 119 were more likely to develop SICH following thrombolysis, whereas patients that received thrombolysis intravenously were less likely to have SICH. These models were free of interactions. 20

20 Table 5. Patient characteristics for those with and without the symptomatic intracranial hemorrhage (SICH) Variable No SICH SICH P (n=432) (n=56) Age, mean (SD) in years 66.52(14) 69.94(11) 0.09 Patients 80 years old, N (%) 68 (15.8) 10 (19.2) 0.5 Female gender, N(%) 192(45) 22(42) 0.7 Caucasian, N(%) 301(75) 34(69) 0.39 Route: IV, N(%) 219(52) 13(25) IA or both 206(48) 38(75) Agent: tpa, N(%) 311(74) 31(60) 0.03 UK or both 95(26) 19(40) NIHSS, mean (SD) 13(7.7) 18(8.5) < MAP, mean (SD) 107.5(19) 113(17.2) Glucose, mean (SD) 137.1(59.4) 179.4(74.4) < Onset to treatment in minutes, 192.1(97.7) 219.5(96.4) mean (SD) History of Smoking, N(%) 86(20) 10(19) 0.93 Hypertension, N(%) 274(63) 41(79)

21 Diabetes, N(%) 89(20) 16(31) 0.31 Stroke, N(%) 91(21) 14(27) 0.62 TIA, N(%) 42(10) 4(8) 0.65 Recanalized, N(%) 183(78) [243]* * [# of cases available for analysis of recanalization] 25(66) [38]* Table 6. Logistic regression models for risk of SICH Outcome measures Predictors Adjusted OR 95% CI P Symptomatic ICH Age IV route MAP > Glucose> Symptomatic ICH Age (age continuous IV route variable) MAP > Glucose> Asymptomatic ICH Among patients who were younger than 80, 18.72% had AICH and among patients that were 80 or older AICH rate was 12.8%. Based on univariate analysis, the following predictors were included in a full main-effect model: age category, thrombolytic agent, route 22

22 of administration, NIHSS on admission, time of treatment, and history of diabetes. Table 8 summarizes a final logistic model. An interaction was found between age and route of administration whether age was dichotomized or continuous variable. Analysis of interaction revealed that only among patients who were younger than 80, the route of thrombolytic administration was associated with about 7 times difference in the risk AICH (OR=7.41; 95% CI: ). Table 9 shows the occurrence AICH after IV or IV/IA therapies in the two age groups. IV/IA or IA alone are associated with significantly higher rates of AICH. Elderly group with AICH had only 10 patients. Advancing age, whether dichotomized or continuous, was not associated with higher rates of AICH. Table 7. Characteristics of patients with asymptomatic intracranial hemorrhage (AICH) or without ICH. Variable AICH No ICH P (n=87) (n=401) Age, mean (SD) in years 65.7 (13.7) 67.2 (13.9) 0.6 Female gender, N(%) 43 (50.6) 171 (43.51) 0.3 Caucasian, N(%) 65 (78.3) 270 (73.6) 0.4 Route: IV, N(%) IA or both 15 (17.9) 69 (82.1) 217 (55.4) 175 (44.6) < Agent: tpa, N(%) UK or both 49 (58.3) 35 (41.7) 293 (78.8) 71 (21.2) < NIHSS, mean (SD) 15.8 (7.5) 13.1(8)

23 MAP, mean (SD) 106.3(21) 108.5(18.4) 0.4 Glucose, mean (SD) (55.89) (64) 0.2 Onset to treatment in minutes, mean (SD) 230.6(93.7) 187.4(97.2) < History of Smoking, N(%) 14 (16.1) 82 (20.5) 0.5 Hypertension, N(%) 53 (60.9) 262 (65.3) 0.5 Diabetes, N(%) 13 (14.9) 92 (22.9) 0.1 Stroke, N(%) 19 (21.8) 86 (21.5) 1.0 TIA, N(%) 6 (6.9) 40 (10) 0.5 Recanalized, N(%) 54 (75) [72]* * [# of cases available for analysis of recanalization] 154 (77) [200]* 0.7 Table 8. Logistic regression models for risks of asymptomatic ICH after thrombolytic therapy. Outcome measures Predictors OR 95% CI P Asymptomatic ICH IV/IA or IA alone in Age < 80 group <

24 Table 9. AICH in different age groups following either IV or IV±IA thrombolysis IV IV/IA or IA P value Age 80, N (%) 5 (50) 5 (50) 0.6 Age<80, N (%) 10 (13.7) 63 (86.3) < Rate of recanalization Among older patients who were evaluated with a cerebral angiogram, the rates of complete or partial recanalization following thrombolytic therapy were similar to those in the younger group; 77% in the younger and 72% in the older groups (Table 3 and 11). Retaining age as a continuous variable did not change the results. The rate of recanalization did not vary in different demographic groups. There was no association of recanalization with history of HTN, DM or smoking (Tables 10 and 111). All routes of thrombolytic administration, IV, IA or a combination had similar recanalization results. There was no difference between age cohorts in full vs. partial recanalization rates. In the selected population as a whole, 24.5% of patients had partial and 52% had complete recanalization. Severity of neurological deficits calculated by NIHSS and blood glucose levels also did not influence the rates of recanalization. 25

25 Table 10. Characteristics of patients who were observed to have recanalization vs. those that did not recanalized Non-Recanalized Recanalized, Variable complete or partial P (n=64) (n=208) Age, mean (SD) in years 68.7 (11.4) (13.2) 0.1 Female gender, N(%) 31 (48.4) 192 (45.07) 0.4 Caucasian, N(%) 46 (74.19) 301 (71.06) 1.0 Route: IV, N(%) IA or both 6 (9.68) 56 (90.32) 24 (12) 176 (88) 0.8 Agent: tpa, N(%) UK or both 40 (62.5) 24 (37.5) 126 (62.1) 77 (37.9) 1.0 NIHSS, mean (SD) 17 (8.9) 15 (7.5) 0.1 MAP, mean (SD) (19.3) (19) 0.6 Glucose, mean (SD) (63.8) (67.4) 0.9 Onset to treatment in minutes, mean (SD) (90.7) (97.6) 0.2 History of Smoking, N(%) 12 (18.8) 35 (16.8) 0.7 Hypertension, N(%) 41 (64) 138 (66.4) 0.8 Diabetes, N(%) 13 (20.3) 46 (22.12)

26 Stroke, N(%) 17 (26.6) 43 (20.7) 0.4 TIA, N(%) 7 (10.9) 18 (8.7) 0.6 Table 11. Logistic regression models for risks of ICH after thrombolytic therapy for patients 80 years of age or older Outcome measures Predictors OR 95% CI P Complete or partial Age recanalization Discussion Our retrospective analysis of prospectively collected data indicates that for every additional 10 years in age for people over 20 years of age the risk of ICH increases by 30%. This means that risk of ICH of a 65 year old is increased by a third when compared to the risk of ICH after thrombolysis in a 55 year old. However, the task of this study was to investigate whether specifically patients over 80 exhibit a higher risk of ICH. This study does not find an association between age over 80 and hemorrhagic transformation after thrombolysis. The uniqueness of our study in that we evaluated outcomes for elderly patients not only after IV thrombolysis within 3 hours but also after IV/IA or IA therapy up to 6 hours from the onset of symptoms. The discrepancy in the results of two regression analyses with and without dichotomizing the variable patient s age is likely to be related to a known fact: categorizing of continuous variables may lead to a significant reduction of power (21). In general, 27

27 information is being lost when a variable is dichotomized. Our study confirms the notion and therefore, both models are discussed. The increase in the risk of ICH after thrombolysis with age is likely to be due to factors related to cerebraovascular changes of aging. For instance, cerebral amyloid angiopathy (CAA) caused by amyloid beta protein deposits in arterial walls is higher in older individuals. CAA is an accepted etiology of lobar ICH in elderly population. Although, it is plausible that CAA can contribute to thrombolysis-related ICH, the direct evidence is lacking (for review see, (22)). The prevalence of CAA is very small in people younger than 50 and it increases significantly after 6 th decade. Another risk factor for ICH after thrombolysis is high arterial blood pressure. In fact, prevalence of hypertension is higher elderly. Based on univariate analysis, we found that our over 80 cohort of patients have significantly higher blood pressure than the younger group. Logistic regression analyses showed that mean arterial pressure was independent predictor of SICH. Therefore, both higher age and blood pressure are associated with higher risk of SICH. The benefits of thrombolysis are well accepted and use of thrombolytic therapy is becoming increasingly common. However, thrombolysis for acute ischemic stroke clinical trials generally excluded patients over 80. Therefore, clinical interest on this subject is focused on the question whether this age group exhibits higher SICH risks. Furthermore, data analysis from use of tpa in clinical trials of myocardial infarction found an association of increasing age and ICH over a decade ago (23). More recent larger database analysis confirmed the findings (24). Therefore, the question of whether patients over 80 are at higher risk deserves our attention and will be discussed below. 28

28 As shown in Table 12, we are in agreement with 8 published studies dealing with IV tpa that showed no statistically significant increase in the risk of SICH patients over 80 (10-12;25-29). Two of these studies included experience at multiple treatment sites, and presumably included patients cared for by physicians with varying training and experience (12;25). Still, their results are consonant with single center studies (26;29). In addition, these studies of IV therapy emphasize that elderly patients have a significantly higher posttreatment mortality than patients younger than the age of 80. Table 12. Symptomatic intracranial hemorrhage and mortality in the elderly after IV or IA thrombolysis for acute ischemic stroke, literature summary Source Route Number of cases SICH No (%) Mortality No (%) Total > 80 > 80 <80 >80 <80 Tanne, et al., 2000 IV (3) 10(6) 6(20) 12(8) Tanne, et al., 2002 IV (9) 3(7.6) NA NA Simon, et.al. IV (9.7) NA 20(32.8) NA Berrouschot, et.al. IV (2.6) 1(2.6) 8(21.1) 10(5.3) Mouradian, et al. IV (9.7) 4(6.2) 10(32.3) 7(10.8) 29

29 Engelter, et al. IV (13) 24(8) 12(32) 35(12) Sylaja, et al. IV (4.4) 40(4.6) 95(35.3) 157(18.2) van Oostenbrugge, et al. IV (11.1) 4(2.9) 18(40) 22(16) Kim, et al. IA (7) 6(8) 35(43) 7(20) UHC BAT Database IV& IA NA NA The rate of SICH in our patients treated with IA thrombolytic agents in the interval between 3 and 6 hours after onset is greater that the rate of SICH in patients treated IV in the first three hours after onset. This pattern is similar to that reported in a combined analysis of outcomes after intravenous tpa administered between 3 and 6 hours after onset (31)(21). Despite the overall increase, the elderly patients do not appear to be selectively vulnerable to SICH at longer intervals after onset. Although elderly patients benefit from arterial thrombolysis, their outcome is worse than for younger groups (10;12;13;25;26;29). Older patients have higher rates of complicating medical conditions such as heart failure, hypertension, and atrial fibrillation (10;12;27). Poor outcomes following ischemic stroke in the elderly could be also due to other factors that are associated with aging. It has been shown in animal and clinical studies that effects of ischemia and reperfusion on brains are hastened in aged organisms (5;6;10;12;27). 30

30 In fact, ischemia challenges the same cellular processes and structures that are weakened by aging itself. Therefore, it is not surprising to discover that older subjects develop significantly larger infarcts. For instance, NINDS rt-pa trial suggested that aged population experienced larger stroke volumes (16). Therefore, there are several reasons unrelated to hemorrhagic complication of thrombolysis that could explain poor outcome of elderly patients. Our analysis confirms findings of other studies that IV/IA and IA therapies produce higher rates of hemorrhagic transformation. The rates of ICH in our study were similar to those reported for IV/IA or IA thrombolysis by other investigators. The published risk of SICH after IA thrombolysis varied between 4.4 % and 18% (7;17;18). Importantly, ICH rates were similar in both of our age cohorts. The higher risk of ICH in the IA or IV/IA groups could be at least in part explained by the increased risk of other hemorrhage-predicting factors present in these cases. The patients that had IA or IV/IA therapy had higher NIHSS, higher blood glucose and about one hour delay in therapy when compared with IV only group. However, in our logistic regression model there were no interactions between time of treatment, glucose or NIHSS with route of administration. Overall, IA therapy presents a great tool for severely affected patients that present up to 6 hours from symptom onset and those that have persistent clot following IV treatments regardless of age. Our study also confirms findings of other publications that symptomatic ICH following thrombolytic therapy could be predicted by high blood pressures and blood glucose levels (7;9;15). Hyperglycemia has a deleterious effect on cerebral vasculature by weakening microvascular integrity especially as a result of reperfusion injury (32). While logistic regression analysis did not reveal an independent association between NIHSS and 31

31 hemorrhage rates, our univariate analysis confirmed previously reported link between the severity of symptoms and ICH (7). Interestingly, there was no such association detected in the older cohort which could be in part due to a small sample size. Rates of AICH in our analysis are similar or lower than those found in other reports (33;34). Our data demonstrated an interaction between the age below 80 and the route of administration in AICH model. Only the younger patients who received IV/IA or IA only thrombolysis had increased rates of AICH. This finding could be due to a small sample size of the elderly cohort. However, it is also possible that even minor hemorrhage is symptomatic in the older group. Another important factor for favorable outcome after stoke is the rate of recanalization. Our analysis suggests that success of recanalization is similar for older and younger patients. The information on rates of recanalization was available only for patients who had angiography for possible IA therapy. These patients generally had persistent severe deficits or those who presented after 3 hours since time of onset. Nonetheless, rates of recanalization in our study are also similar to those found in the literature (35-37) and reflect success of interventional angiography in our center. Overall, it is likely that poor outcomes following stroke are not simply due to failure to respond to thrombolysis. As any retrospective study, our analysis is subject to limitations and bias. However, one advantage is that all data collection was prospective and performed at the time of patient treatment. This is a single center data collection and therefore, sample size of the elderly group is rather limited. A small size was likely a cause of high variance, therefore, a larger sample collection is warranted to confirm our findings. A relatively small sample size of the elderly cohort may be a reason for a lack of association of NIHSS and time of treatment with 32

32 the route of thrombolytic administration. The younger group with SICH that had IA or both therapies had a higher NIHSS and longer time to treatment. Another limitation is that our data on recanalization is limited for those who had IA thrombolysis only and only available for patients that were taken to angiography. These patients generally have more severe deficits. Therefore, it is possible that our overall rates of recanalization are much greater. In addition, there is a potential bias in our work that is hard to quantify. As with any center that provides care for patients who present elsewhere first, we cannot exclude the possibility that physicians outside our institution are consciously or unconsciously selecting patients who are to be considered for therapy. A similar concern was noted by Tanne and colleagues (27), who pointed out that elderly patients in their institution were disproportionately referred by stroke specialists. Primary care physicians or emergency room physicians may have been unwilling to refer frail, elderly patients for therapy. However, in spite of the limitation our analysis provides important information for a group of patients that suffer the most and could benefit greatly from a multimodal acute treatment that is being provided by many centers throughout the world. In summary, our data suggest that patients over 80 years of age do not have increased rates of post-thrombolytic complications and therefore may be treated when indicated with IV, IA or IV/IA thrombolytic therapies. However, we also confirmed that there is an agerelated risk of SICH when age is tested as a continuous variable. Larger cohort analyses may be needed to further test this hypothesis. Furthermore, our findings emphasized that glycemic and blood pressure control remain important facets of acute stroke management and should be investigated further. 33

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