<abstract xmlns="http://www.w3.org/1999/xhtml"><sec id="j_1905-7415.0903.409_s_001_w2aab3b7c15b1b6b1aab1c16b1Aa"><h3>Background</h3><p>Acute stroke is a common neurological disorder. Intravenous recombinant tissue-type plasminogen activator (rt-PA) treatment is recommended for treatment of patients with acute ischemic stroke. A major side effect of rt-PA is intracerebral hemorrhage (ICH). Studies of the risks for ICH after rt-PA treatment in Asian populations are limited.</p></sec><sec id="j_1905-7415.0903.409_s_002_w2aab3b7c15b1b6b1aab1c16b2Aa"><h3>Objective</h3><p>To determine risk factors for intracerebral hemorrhage after treatment of acute ischemic stroke with rt-PA and create online tool to calculate the risk.</p></sec><sec id="j_1905-7415.0903.409_s_003_w2aab3b7c15b1b6b1aab1c16b3Aa"><h3>Methods</h3><p>We reviewed all patients with acute ischemic stroke who received treatment with rt-PA within 4.5 hours of stroke onset at the stroke fast track unit, Srinagarind Hospital, Khon Kaen University, Thailand. The study period was between November 2008 and September 2011. Factors associated with ICH after rt-PA treatment were analyzed by multivariate logistic regression.</p></sec><sec id="j_1905-7415.0903.409_s_004_w2aab3b7c15b1b6b1aab1c16b4Aa"><h3>Results</h3><p>There were 162 patients with acute ischemic stroke who received rt-PA treatment within 4.5 hours. Of those, 12 patients (7.41%) developed ICH. Only baseline modified Rankin scale score was significantly associated with ICH. The adjusted odds ratio was 1.733 (95% CI 1.008 to 2.982). An online tool to calculate the risk is available at <ext-link ext-link-type="uri" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://202.28.94.20/research/">http://202.28.94.20/research/</ext-link>.</p></sec><sec id="j_1905-7415.0903.409_s_005_w2aab3b7c15b1b6b1aab1c16b5Aa"><h3>Conclusions</h3><p>Intracerebral hemorrhage after rt-PA treatment of patients with acute stroke was low at 7.41% and related to baseline functional status.</p></sec></abstract>

BackgroundAcute stroke is a common neurological disorder. Intravenous recombinant tissue-type plasminogen activator (rt-PA) treatment is recommended for treatment of patients with acute ischemic stroke. A major side effect of rt-PA is intracerebral hemorrhage (ICH). Studies of the risks for ICH after rt-PA treatment in Asian populations are limited.ObjectiveTo determine risk factors for intracerebral hemorrhage after treatment of acute ischemic stroke with rt-PA and create online tool to calculate the risk.MethodsWe reviewed all patients with acute ischemic stroke who received treatment with rt-PA within 4.5 hours of stroke onset at the stroke fast track unit, Srinagarind Hospital, Khon Kaen University, Thailand. The study period was between November 2008 and September 2011. Factors associated with ICH after rt-PA treatment were analyzed by multivariate logistic regression.ResultsThere were 162 patients with acute ischemic stroke who received rt-PA treatment within 4.5 hours. Of those, 12 patients (7.41%) developed ICH. Only baseline modified Rankin scale score was significantly associated with ICH. The adjusted odds ratio was 1.733 (95% CI 1.008 to 2.982). An online tool to calculate the risk is available at http://202.28.94.20/research/.ConclusionsIntracerebral hemorrhage after rt-PA treatment of patients with acute stroke was low at 7.41% and related to baseline functional status.

<div xmlns="http://www.w3.org/1999/xhtml"><p>Acute stroke is the most common neurological disorder worldwide. Its incidence is approximately 9 million people per year (WHO) with a mortality of 64.21 persons/100,000 population [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_001_w2aab3b7c15b1b6b1ab1b7b1Aa">1</a>]. The incidence is increasing. Stroke may cause neurological sequelae and disability. It is ranked as 6<sup>th</sup> for disease causing morbidity.</p><p>Intravenous recombinant tissue-type plasminogen activator (rt-PA) treatment is recommended for patients with acute ischemic stroke. The newly described “golden period” for rt-PA treatment is 4.5 hours after stroke occurrence [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_002_w2aab3b7c15b1b6b1ab1b7b2Aa">2</a>]. Compared with placebo, rt-PA treatment improves clinical outcome. However, symptomatic intracerebral hemorrhage occurs more frequently in the rt-PA group (2.4% vs 0.2%; <italic>P</italic> = 0.008). Risk factors for intracerebral hemorrhage after rt-PA treatment have been explored. Functional status and infarct size may increase the risk of intracerebral hemorrhage after rt-PA treatment [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_002_w2aab3b7c15b1b6b1ab1b7b2Aa">2</a>]. However, in the Thai population these data are limited, particularly after the new “golden period” era.</p><sec id="j_1905-7415.0903.409_s_006_w2aab3b7c15b1b6b1ab1b2Aa"><div>Methods</div><p>The study protocol was approved by the Khon Kaen University Ethics Committee for Human Research (approval No. HE541372).</p><p>We reviewed the cases of all patients with acute ischemic stroke who received treatment with rt-PA within 4.5 hours of stroke onset at the stroke fast track unit, Srinagarind Hospital, Khon Kaen University, Thailand. The study period was November 2008 and September 2011. This study used the same dataset as that in a previously published article [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_003_w2aab3b7c15b1b6b1ab1b7b3Aa">3</a>].</p><p>All baseline clinical features were recorded including age, sex, baseline National Institutes of Health Stroke Scale (NIHSS) [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_004_w2aab3b7c15b1b6b1ab1b7b4Aa">4</a>], baseline modified Rankin scale (mRS) [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_005_w2aab3b7c15b1b6b1ab1b7b5Aa">5</a>], time from the onset of symptoms to computed tomography (CT) of the brain in minutes, time from the onset to rt-PA treatment, Alberta Stroke Program Early CT score (ASPECTS) [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_003_w2aab3b7c15b1b6b1ab1b7b3Aa">3</a>], and characteristics of CT brain findings.</p><p>Patients were divided into two groups; with or without intracerebral hemorrhage as seen by the summary discharge sheet. Baseline and clinical characteristics of patients between both groups were compared using descriptive statistics. Univariate logistic regression analyses were applied to calculate the crude odds ratios (OR) of individual variables for having intracerebral hemorrhage. All clinically significant variables or <italic>P</italic> &lt; 0.20 by univariate analyses were included in subsequent multivariate logistic regression analyses. Analytical results were presented as crude OR, adjusted OR, and 95% confidence intervals (CI). Data analyses were performed with STATA software (College Station, TX, USA).</p><p>An online tool to predict the risk for intracerebral hemorrhage after rt-PA treatment was produced by using the final model of multivariate logistic regression analysis. The probability equals 1/[1+e<sup>–x</sup>]. X refers to the constant value and coefficient value of all factors in the final model.</p></sec><sec id="j_1905-7415.0903.409_s_007_w2aab3b7c15b1b6b1ab1b3Aa"><div>Results</div><p>There were 162 patients with acute ischemic stroke who received rt-PA treatment within 4.5 hours. Of those, 12 patients (7.41%) developed intracerebral hemorrhage. Patients with intracerebral hemorrhage had comparable clinical features to those who did not have intracerebral hemorrhage (<bold><a ref-type="table" href="#j_1905-7415.0903.409_tab_001_w2aab3b7c15b1b6b1ab1b3b2Ab2">Table 1</a></bold>). However, the baseline NIHHS, and the baseline mRS were higher in those who had intracerebral hemorrhage (NIHHS: 13 vs 9.5; mRS: 4 vs 3) than those who did not have intracerebral hemorrhage. By multivariate logistic regression analysis, only baseline mRS was significantly associated with having intracerebral hemorrhage. The adjusted odds ratio was 1.733 (95% CI 1.008 to 2.982).</p><table-wrap position="float" orientation="portrait" id="j_1905-7415.0903.409_tab_001_w2aab3b7c15b1b6b1ab1b3b2Ab2"><label>Table 1</label><caption><p>Clinical factors between patients with acute stroke who received rt-PA treatment within 4.5 hours categorized by the occurrence of intracerebral hemorrhage (ICH)</p></caption><table rules="groups"><thead><tr><th align="left">Variables</th><th align="left">No hemorrhage (n = 150)</th><th align="left">ICH (n = 12)</th><th align="left"><italic>P</italic></th></tr></thead><tbody><tr><td align="left">Age, years</td><td align="left">65 (55-74)</td><td align="left">71 (55.50-7 5 )</td><td align="left">0.616</td></tr><tr><td align="left">Male sex, n</td><td align="left">80 (53.33)</td><td align="left">4 (33.33)</td><td align="left">0.235</td></tr><tr><td align="left">Baseline NIHHS</td><td align="left">9.5 (6-13)</td><td align="left">13 (7.5-1 6 )</td><td align="left">0.092</td></tr><tr><td align="left">Baseline mRS</td><td align="left">3 (2-4)</td><td align="left">4 (3-4.5)</td><td align="left">0.081</td></tr><tr><td align="left">Time to CT, min</td><td align="left">86.5 (64-116)</td><td align="left">99 (76-162)</td><td align="left">0.390</td></tr><tr><td align="left">Time to rt-PA, min</td><td align="left">128.5 (103-161)</td><td align="left">139 (116 -202)</td><td align="left">0.443</td></tr><tr><td align="left">Received rt-PA 3-4.5 hour</td><td align="left">25 (16.67)</td><td align="left">4 (33.33)</td><td align="left">0.230</td></tr><tr><td align="left">ASPECTS score</td><td align="left">7 (5-9)</td><td align="left">7 (5-8.5)</td><td align="left">0.628</td></tr><tr><td align="left">Dense MCA</td><td align="left">43 (28.67)</td><td align="left">3 (25.00)</td><td align="left">0.999</td></tr><tr><td align="left">Caudate lesion</td><td align="left">53 (35.33)</td><td align="left">6 (50.00)</td><td align="left">0.357</td></tr><tr><td align="left">Left side lesion</td><td align="left">57 (38.00)</td><td align="left">5 (41.67)</td><td align="left">0.999</td></tr></tbody></table><table-wrap-foot><p>Data presented as median (1<sup>st</sup> and 3<sup>rd</sup> quartile) or numbers (percentage), NIHHS = National Institutes of Health Stroke Scale, mRS = modified Rankin scale, CT = computed tomography, rt-PA = recombinant tissue-type plasminogen activator, ASPECTS = Alberta Stroke Program Early CT score, MCA = middle cerebral artery</p></table-wrap-foot></table-wrap><p>An online tool is available at <ext-link ext-link-type="uri" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://202.28.94.20/research/">http://202.28.94.20/research/</ext-link>. The X value in the formula was calculated using the following equation; X = –4.07 + [0.56 × mRS] – [0.68 × dense middle cerebral artery; 0 if no, 1 if yes] – [0.005 × time to CT in minute] + [1.46 × rt-PA treatment period; 0 if less than 3 hours, and 1 for 3 to 4.5 hours].</p></sec><sec id="j_1905-7415.0903.409_s_008_w2aab3b7c15b1b6b1ab1b4Aa"><div>Discussion</div><p>Use of streptokinase in treatment of acute ischemic stroke is prone to adverse reactions [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_006_w2aab3b7c15b1b6b1ab1b7b6Aa">6</a>]. A randomized, placebo-controlled trial of streptokinase was stopped early because of an increased risk of intracerebral hemorrhage. The mortality and disability outcome between streptokinase and the placebo groups was not different at six months. However, patients in the streptokinase group had significantly higher mortality at 10 days after treatment (34.0% vs 18.2%). Intracerebral hemorrhage was 21.2% vs 2.6% in the placebo group. At present, rt-PA is considered an effective and safer thrombolytic agent for acute ischemic stroke treatment than streptokinase [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_002_w2aab3b7c15b1b6b1ab1b7b2Aa">2</a>]. Nevertheless, intracerebral hemorrhage remains an important side effect, even with rt-PA.</p><p>The rate of intracerebral hemorrhage after rt-PA treatment is 7.41%, which was somewhat higher than previous reports [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_002_w2aab3b7c15b1b6b1ab1b7b2Aa">2</a>, <a ref-type="bibr" href="#j_1905-7415.0903.409_ref_007_w2aab3b7c15b1b6b1ab1b7b7Aa">7</a>]. A report from central Thailand found the rate was 5.7% in 192 patients who received rt-PA treatment in the new window period as used in this study [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_008_w2aab3b7c15b1b6b1ab1b7b8Aa">8</a>].</p><p>There are several risk scores to predict risk of intracerebral hemorrhage, such as the H AT score [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_009_w2aab3b7c15b1b6b1ab1b7b9Aa">9</a>], the DRAGON score [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_010_w2aab3b7c15b1b6b1ab1b7c10Aa">10</a>], or the SEDAN score [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_011_w2aab3b7c15b1b6b1ab1b7c11Aa">11</a>]. The DRAGON and SEDAN scores suggested that a dense middle cerebral artery sign is a predictor for intracerebral hemorrhage after rt-PA treatment, but not in this study. The HAT and SEDAN score had NIHHS score as a significant predictor. The present study showed that mRS score is the only predictor for intracerebral hemorrhage after rt-PA treatment. The mRS may be similar to NIHHS score in terms of functional status evaluation before rt-PA treatment. These mentioned scores are derived from studies conducted in the Western countries. The HAT score is valid for predicting the risk of intracerebral hemorrhage after rt-PA treatment in Taiwanese patients [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_012_w2aab3b7c15b1b6b1ab1b7c12Aa">12</a>]. A study from Thailand found that atrial fibrillation, and NIHHS were associated with (asymptomatic) post rt-PA treatment intracerebral hemorrhage. It seems that baseline functional status may be a clinical predictor for post rt-PA treatment intracerebral hemorrhage; either NIHHS ≥15 or high mRS score. An increase in mRS score at baseline of 1 will increase the risk of intracerebral hemorrhage by 1.75 times (<bold><a ref-type="table" href="#j_1905-7415.0903.409_tab_002_w2aab3b7c15b1b6b1ab1b4b4Ab2">Table 2</a></bold>). An online tool is provided by the final model of multivariate logistic regression by this study.</p><table-wrap position="float" orientation="portrait" id="j_1905-7415.0903.409_tab_002_w2aab3b7c15b1b6b1ab1b4b4Ab2"><label>Table 2</label><caption><p>Clinical factors between patients with acute stroke who received rt-PA treatment within 4.5 hours categorized by the occurrence of intracerebral hemorrhage (ICH)</p></caption><table rules="groups"><thead><tr><th align="left">Variables</th><th align="left">Univariate odds ratio (95% CI)</th><th align="left">Adjusted odds ratio (95% CI)</th></tr></thead><tbody><tr><td align="left">Baseline mRS score</td><td align="left">1.535 (0.927 to 2.542)</td><td align="left">1.746 (1.008 to 3.023)</td></tr><tr><td align="left">Dense middle cerebral artery</td><td align="left">0.829 (0.214 to 3.211)</td><td align="left">0.505 (0.118 to 2.153)</td></tr><tr><td align="left">Time to computed tomography</td><td align="left">1.005 (0.994 to 1.018)</td><td align="left">0.995 (0.975 to 1.016)</td></tr><tr><td align="left">Received rt-PA within 3–4.5 hours</td><td align="left">2.500 (0.699 to 8.944)</td><td align="left">4.304 (0.407 to 45.530)</td></tr></tbody></table><table-wrap-foot><p>mRS = modified Rankin scale, rt-PA = recombinant tissue-type plasminogen activator, CI = confidence interval</p></table-wrap-foot></table-wrap><p>Baseline NIHHS score is used as a contraindication for rt-PA treatment. A baseline NIHHS score more than 25 is not eligible for rt-PA treatment [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_002_w2aab3b7c15b1b6b1ab1b7b2Aa">2</a>]. In addition, baseline NIHHS and ASPECTS scores are factors associated with long term functional outcomes in patients who have suffered from an acute stroke. However, neither factor is associated with the risk for intracerebral hemorrhage after rt-PA treatment in this study by either univariate or multivariate logistic regression analyses. Only mRS score was significantly associated with intracerebral hemorrhage. The mRS score is more practical to determine than NIHHS and ASPECTS scores in clinical practice [<a ref-type="bibr" href="#j_1905-7415.0903.409_ref_003_w2aab3b7c15b1b6b1ab1b7b3Aa">3</a>].</p><p>In conclusion, baseline functional status may associate with intracerebral hemorrhage after rt-PA treatment in acute stroke patients.</p></sec></div>

Risk factors for intracerebral hemorrhage after treatment with recombinant tissue-type plasminogen activator for acute ischemic stroke

Department of Radiology, Faculty of Medicine

Department of Medicine, Faculty of Medicine

Research Center in Back, Neck Other Joint Pain and Human Performance (BNOJPH)

Asian Biomedicine

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

BackgroundAcute stroke is a common neurological disorder. Intravenous recombinant tissue-type plasminogen activator (rt-PA) treatment is recommended for...

Risk factors for intracerebral hemorrhage after treatment with recombinant tissue-type plasminogen activator for acute ischemic stroke

Article Category: Brief communication (Original)

Published Online: Jan 31, 2017

Page range: 397 - 400

DOI: https://doi.org/10.5372/1905-7415.0903.409

Keywords
Acute stroke, complication, intracerebral hemorrhage, ischemic, modified Rankin scale, recombinant tissue-type plasminogen activator, rt-PA, thrombolytic

© 2015 Warinthorn Phuttharak, Kittisak Sawanyawisuth, Boonrerk Sangpetngam, Somsak Tiamkao, Kannikar Kongbunkiat, Verajit Chotmongkol, Panita Limpawattana, Theerayut Thongkrau, Chaiyapon Keeratikasikorn

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Clinical factors between patients with acute stroke who received rt-PA treatment within 4.5 hours categorized by the occurrence of intracerebral hemorrhage (ICH)

Variables	Univariate odds ratio (95% CI)	Adjusted odds ratio (95% CI)
Baseline mRS score	1.535 (0.927 to 2.542)	1.746 (1.008 to 3.023)
Dense middle cerebral artery	0.829 (0.214 to 3.211)	0.505 (0.118 to 2.153)
Time to computed tomography	1.005 (0.994 to 1.018)	0.995 (0.975 to 1.016)
Received rt-PA within 3–4.5 hours	2.500 (0.699 to 8.944)	4.304 (0.407 to 45.530)

Risk factors for intracerebral hemorrhage after treatment with recombinant tissue-type plasminogen activator for acute ischemic stroke

Article Category: Brief communication (Original)

Published Online: Jan 31, 2017

Page range: 397 - 400

DOI: https://doi.org/10.5372/1905-7415.0903.409

KeywordsAcute stroke, complication, intracerebral hemorrhage, ischemic, modified Rankin scale, recombinant tissue-type plasminogen activator, rt-PA, thrombolytic

© 2015 Warinthorn Phuttharak, Kittisak Sawanyawisuth, Boonrerk Sangpetngam, Somsak Tiamkao, Kannikar Kongbunkiat, Verajit Chotmongkol, Panita Limpawattana, Theerayut Thongkrau, Chaiyapon Keeratikasikorn

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Clinical factors between patients with acute stroke who received rt-PA treatment within 4.5 hours categorized by the occurrence of intracerebral hemorrhage (ICH)

Keywords
Acute stroke, complication, intracerebral hemorrhage, ischemic, modified Rankin scale, recombinant tissue-type plasminogen activator, rt-PA, thrombolytic