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Temporal Trends in Intravenous Thrombolysis in Acute Ischemic Stroke: Experience from a Tertiary Care Center in India
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Temporal Trends in Intravenous Thrombolysis in Acute Ischemic Stroke: Experience from a Tertiary Care Center in India Dheeraj Khurana, MD, DM,* Biplab Das, DM,* Ashok Kumar, MD,* Amith Kumar S., MD,* Niranjan Khandelwal, MD,† Vivek Lal, DM,* and Sudesh Prabhakar, DM*
Background: Acute ischemic stroke (AIS) is a time-dependent treatable cause of morbidity and mortality. Despite the increasing stroke incidence in developing countries, parallel increasing stroke thrombolysis rates have not been documented. Aim: This study aims to determine trends in patient characteristics and rates of recombinant tissue plasminogen activator (rtPA) use in AIS patients in a tertiary care center in northern India. Methods: All AIS patients presenting within 8 hours of symptoms onset from January 2011 to December 2015 were enrolled and analyzed. Results: A total of 867 AIS patients presented within 8 hours of symptoms onset. Out of 593 eligible patients, 189 (31.87%) underwent intravenous thrombolysis (IVT) with rtPA within 4.5 hours of the window period. Patients (undergoing) IVT had onset-to-door times of 2 hours or less (23.81%), 2-3 hours (33.86%), and 3.0-4.5 hours (42.33%). IVT rates in 2 hours or less of symptom onset increased from 22% to 25% and IVT rates in 2-3 hours increased from 38.9% to 43.8%. Door-tocomputerized tomographic time (median 27 versus 11 minutes, P = .0001) and doorto-needle time (median 83 versus 67 minutes, P = .011) improved, with a significant improvement of computerized tomography imaging time within 25 minutes of arrival (from 50% to 78.4%, P = .014). Post-IVT symptomatic hemorrhage was noted in 5 patients (2.65%). The median National Institutes of Health Stroke Scale score at presentation was 11, whereas a favorable modified Rankin Scale score (0-1) at 3 months was seen in 39.68%. Conclusions: Encouraging trends in IVT over the years may be indicative of increasing community awareness of stroke and improving quality of stroke care in developing countries such as India. Key Words: Stroke—intravenous thrombolysis—rtPA—trends—developing countries. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; and †Department of Radiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Received November 8, 2016; revision received January 17, 2017; accepted January 20, 2017. D.K. and B.D. have equal first authorship. Address correspondence to Dheeraj Khurana, MD, DM, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.01.019
Eligibility for acute ischemic stroke (AIS) interventions depends on the time from symptom onset to hospital arrival. Only a minority of patients arrived early enough to be considered for acute therapy, and most studies describe experiences of specific centers or regional networks over a limited time period.1 Many patients without documented contraindications still do not receive intravenous (IV) recombinant tissue plasminogen activator (rtPA), despite being currently the only approved medical treatment for patients with AIS within 4.5 hours of stroke onset.1,2 Worldwide, professional
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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societies, different state and government agencies, and national patient support organizations are making efforts to increase rtPA use in eligible patients.3 Although studies in developed countries have demonstrated significant improvement in trends in intravenous thrombolysis (IVT), there are limited data from developing countries and the Indian subcontinent.4 The present study highlights trends in IV rtPA use over 5 years in a large tertiary care hospital in North India.
Methods Case Definition The stroke onset times were recorded as the time the patient was last known to be well and the time that symptom onset was discovered; approximate times were not allowed. The onset-to-door (OTD) time was defined as the time the patient arrived in the emergency department (ED) minus the stroke onset time. The onset-toneedle time (OTN) was equivalent to the window period, whereas the door-to-needle time was the time taken to start IVT after reaching the hospital. Thrombolysisinduced symptomatic intracranial hemorrhage was defined as a type 2 parenchymal hemorrhage with deterioration with a National Institutes of Health Stroke Scale (NIHSS) score of 4 points or higher or death, within 36 hours of thrombolysis (as per Safe Implementation of Thrombolysis in Stroke-Monitoring Study [SITS-MOST]).5
Patient Population The primary objective of the study was to evaluate the changes in the patterns of use of IVT over a 5-year period from January 2011 to December 2015. We report data of all AIS patients who were treated with IVT within 4.5 hours of symptom onset. Data were derived from our hospital stroke registry and the Safe Implementation of Treatments in Stroke (SITS)—India registry, where our hospital data were also registered. Our stroke team comprised neurology and neuroradiology physicians, fellows, and stroke nurses and had been in place before 2011. Acute stroke notification of the stroke team members was provided by emergency mobile notification. Stroke team members rotate on “first call” and are available 24 × 7. A regular education program of residents and nurses is carried out to train them on early and accurate recognition of acute stroke patients and to institute an acute stroke management pathway that includes immediate notification of our stroke team and early evaluation of patient and assessment of the usual exclusions to rtPA. In all eligible patients of thrombolysis, baseline blood pressure and blood sugar levels were determined and rapid coagulogram (point of care) was carried out before rtPA bolus dose. Data were recorded in a brief acute stroke card listing patients’ demographics, stroke type, intervals, and other critical
Figure 1. Recruitment profile of an acute ischemic stroke patient and thrombolysis window period. Abbreviation: IVT, intravenous thrombolysis.
information pertaining to thrombolysis. The platelet counts were immediately ordered, but IVT was started while the report was awaited, with instructions to stop IVT in case of low platelet counts. All patients were closely monitored closely in the post-thrombolytic period as per guidelines.6 Patients receiving IVT were divided into the following groups: within (1) 2 hours, (2) 2-3 hours, and (3) 3.0-4.5 hours. Patients treated after 4.5 hours of the window period were not included in the analysis. A total of 196 patients underwent IVT during this period; 7 patients were excluded as IVT was carried out after 4.5 hours (posterior circulation stroke) (Fig 1).
Imaging All patients underwent a cranial CT scan with CT angiography. All patients underwent a follow-up CT scan at 24 hours of IVT. We have not included the CT angiographic data in the present study.
Statistical Analysis For each of the 3 patient groups, demographics and clinical variables were analyzed (Table 1). Temporal trends were explored for the groups treated with IV rtPA within 4.5 hours of onset by calendar year from 2011 through December 2015 (Table 2).Yearly trends over time in OTN were tabulated according to the following categories: OTN time of 2 hours, OTN time of 2-3 hours, and OTN time
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Table 1. Baseline characteristics and thrombolysis-related parameters
Patients characteristics
All AIS patients within 8 h (n = 867)
All IVT (OTN ≤4.5 h) (n = 189)
IVT (OTN ≤2 h) (n = 45)
IVT (OTN 2-3 h) (n = 64)
IVT (OTN 3.0-4.5 h) (n = 80)
Demographics Age (years), median (IQR), n (%)
60 (50.0-70.5)
60 (49-72)
60 (47.5-65.5)
61 (50.0-71.75)
104 (12) 359 (41.4) 336 (38.8) 68 (7.8)
22 (11.6) 75 (39.7) 78 (41.3) 14 (7.4)
4 (8.9) 19 (42.2) 19 (42.2) 3 (6.7)
7 (10.9) 24 (37.5) 28 (43.8) 5 (7.8)
59.5 (49.25-73.75) P = .908 11 (13.8) 32 (40) 31 (38.8) 6 (7.5) P = .988
Sex, n (%) Men Women
574 (66.2) 293 (33.8)
124 (65.6) 65 (34.4)
30 (66.7) 15 (33.3)
39 (60.9) 25 (39.1)
55 (68.8) 25 (31.2) P = .609
Transport facility, n (%) Ambulance Own vehicle Public vehicle In-hospital
201 (23.2) 430 (49.6) 148 (17.1) 88 (10.1)
42 (22.2) 109 (57.7) 14 (7.4) 24 (12.7)
5 (11.1) 26 (57.8) 2 (4.4) 12 (26.7)
8 (12.5) 43 (67.2) 6 (9.4) 7 (10.9)
29 (36.2) 40 (50.1) 6 (7.5) 5 (6.2) P = .001
Occupation, n (%) Government employee or retired Private employee or laborer Unemployed or housewife
268 (30.9) 157 (18.1) 442 (51)
58 (30.7) 37 (19.6) 94 (49.7)
13 (28.9) 7 (15.6) 25 (55.6)
17 (26.6) 13 (20.3) 34 (53.1)
28 (35) 17 (21.2) 35 (43.8) P = .663
Habitat, n (%) Rural Semiurban Urban
174 (20.1) 104 (12) 589 (67.9)
38 (20.1) 24 (12.7) 127 (67.2)
9 (20) 7 (15.6) 29 (64.4)
13 (20.3) 6 (9.4) 45 (70.3)
Atrial fibrillation, n (%)
156 (18)
36 (19.0)
10 (22.2)
13 (20.3)
Hypertension, n (%)
468 (54)
104 (55.0)
23 (51.1)
39 (60.9)
CAD or previous MI, n (%)
189 (21.8)
35 (18.5)
5 (11.1)
12 (18.8)
Diabetes mellitus, n (%)
208 (24)
45 (23.8)
8 (17.8)
17 (26.6)
Smoking, n (%)
225 (25.9)
46 (24.3)
15 (33.3)
8 (12.5)
Prior CVA or TIA, n (%)
131 (15.1)
30 (15.9)
6 (13.3)
8 (12.5)
11 (5-20)
11 (6-18)
11 (6.5-17)
12 (6-17)
16 (20) 11 (13.8) 53 (66.2) P = .902 13 (16.2) P = .682 42 (52.2) P = .499 18 (22.5) P = .290 20 (25) P = .540 23 (28.8) P = .021 16 (20) P = .410 11 (7.25-20) P = .630
Baseline NIHSS levels, n (%) 0-7 8-12 13-25 Higher than 25
276 (31.8) 202 (23.4) 322 (37.1) 67 (7.7)
58 (30.7) 48 (25.4) 70 (37.0) 13 (6.9)
14 (31.1) 12 (26.7) 18 (40) 1 (2.2)
24 (37.5) 12 (18.8) 24 (37.5) 4 (6.2)
OTD (min), median (IQR)
168 (86-295)
91 (55-143.5)
35 (15-60)
DTCT time (min), median (IQR)
NA
17 (10-30)
15 (9-25)
15 (8-28)
DTCT time (≤25 min)
NA
133 (70.4%)
37 (82.2%)
46 (71.9%)
OTN (min), median (IQR)
NA
165 (127.5-225)
100 (78-110)
150 (135-165)
DTN (min), median (IQR)
NA
63 (48.5-85)
55 (41-65)
DTN (≤60 min)
NA
89 (47.1%)
31 (68.9%)
40 or under 41-60 61-80 Over 80
Baseline NIHSS score, median (IQR)
80.5 (62-95.75)
69.5 (50.25-88.75) 25 (39.1%)
20 (25) 24 (30) 28 (35) 8 (10) P = .397 154 (116.25-179) P = .0001 22 (10-36) P = .051 50 (62.5%) P = .065 230 (210-250) P = .0001 66 (48.5-103) P = .002 33 (41.2%) P = .003
Abbreviations: AIS, acute ischemic stroke; CAD, coronary artery disease; CVA, cerebrovascular accident; DTCT, door to computerized tomographic; DTN, door to needle; IQR, interquartile range; IVT, intravenous thrombolysis; MI, myocardial infarction; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale; OTD, onset to door; OTN, onset to needle; TIA, transient ischemic attack.
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Table 2. Trend of different thrombolysis-related parameters from January 2011 to December 2015
Hemorrhage SICH IVT-related death (in-hospital)
2011
2012
2013
2014
2015
P value
189 60 (49-72) 124/65 91 (55.0-143.5) 17 (10-30) 63 (48.5-85.0) 165 (1275-225) 104 45 36 30 35 46 11 (6-18) 75
18 59.5 (46.5-70.5) 14/4 83 (52.5-101.25) 27 (15-35) 82.5 (58.75-116.25) 167.5 (123.75-246.25) 9 (50) 2 (11.1) 3 (16.7) 1 (5.6) 2 (11.1) 4 (22.2) 13 (5-23) 8 (44.4)
33 65 (52-75.5) 28/5 81 (45.0-147.5) 25 (20.5-39.0) 78 (58-105) 185 (137.5-235.0) 21 (63.3) 8 (24.2) 5 (15.2) 6 (18.2) 8 (24.2) 8 (24.2) 15 (10-23) 14 (42.4)
53 65 (46-75) 30/23 92 (57.5-151) 18 (10.0-29.5) 56 (47-80) 150 (117.5-220.0) 32 (60.4) 13 (24.5) 8 (15.1) 5 (9.4) 11 (20.8) 9 (17) 11 (6-17) 23 (43.4)
48 60 (50-71.75) 30/18 91.5 (50.75-127) 11 (5-17) 60 (45.0-78.75) 152.5 (121.25-202.5) 23 (47.9) 15 (31.3) 12 (25) 11 (22.9) 8 (16.7) 14 (29.2) 11 (6-16) 17 (35.4)
37 58 (45-63.5) 22/15 95 (73-160) 11 (8.0-23.5) 67 (47.5-80.0) 195 (135-230) 19 (51.4) 7 (18.9) 8 (21.6) 7 (18.9) 6 (16.2) 11 (29.7) 10 (5.0-16.5) 13 (43.3) N = 30 2 (5.4) 2 3
.0001 .169 .053 F .581 .0001 .011 .238 .563 .500 F .726 F .270 F .810 F .586 F .121 .921
25 5 18
2 (11.1) 0 1
5 (15.2) 0 2
8 (15.1) 0 6
8 (16.7) 3 6
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Number of patients Age (years), median (IQR) Sex (M/F) OTD (min), median (IQR) DTCT (min), median (IQR) DTN (min), median (IQR) OTN (min), median (IQR) HTN DM AF Previous CVA or TIA CAD or MI Smoking Baseline NIHSS score, median (IQR) mRS score (0-1)
All IVT
.569 F
Abbreviations: AF, arterial fibrillation; CAD, coronary artery disease; CVA, cerebrovascular accident; DM, diabetes mellitus; DTCT, door to computerized tomographic; DTN, door to needle; F, female; HTN, hypertension; IQR, interquartile range; IVT, intravenous thrombolysis; M, male; MI, myocardial infarction; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OTD, onset to door; OTN, onset to needle; SICH, symptomatic intracerebral hemorrhage; TIA, transient ischemic attack. D. KHURANA ET AL.
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Figure 2. Trend of outcome (mRS score) of patients receiving intravenous recombinant tissue plasminogen activator within 4.5 hours of ischemic stroke at 90 days. Abbreviation: mRS, modified Rankin Scale.
of 3.0-4.5 hours. Continuous variables were compared by Kruskal–Wallis test. Categorical variables were compared by χ2 test. Predictors of early arrival (≤2 hours) and good outcome (modified Rankin Scale [mRS] score 0-1) were identified using multivariable analysis (Tables 3, 4).
Results From January 2011 to December 2015, 867 patients of AIS who presented within 8 hours of stroke were recruited in the study and 189 (31.87%) patients underwent IVT out of 593 eligible candidates (presenting within 4.5 hours of window period). Common causes for exclusion were financial constraint, high cost of rtPA, and negative consent. Age and sex distributions were similar across the cohorts (Table 1). However, compared to female patients, twice the number of male patients underwent thrombolysis. Seven percent of the patients were over 80 years of age, whereas no significant preferred age group was observed in patients who underwent thrombolysis. Ambulance was used in 23.2% to bring patients to the hospital, whereas 22.2% of rtPA-treated patients used an ambulance. Most patients (57.7%) used a private vehicle to reach the hospital. Majority of the thrombolysed patients were from urban areas, but no major difference was noted in early reporting to hospital compared to patients from rural areas. Atrial fibrillation was seen in ~20% patients. There was no significant difference in the initial median NIHSS score in the rtPA-eligible and rtPAtreated groups compared to all AIS patients. More than 40% of the patients had a severe stroke (NIHSS score >12), whereas 6.9% had an NIHSS score higher than 25. Subanalysis of data showed that patients with severe strokes tended to report early.
In univariate analysis, rtPA use changed over time across most patient characteristics measured, with a pattern of expanding the treated population into a broader range (Table 1). The number of patients receiving rtPA aged over 80 years increased over the years. There were significant improvements in the trend of rtPA use in women (from 22.2% to 40.54%, P = .031). Over the years, the trend in effective thrombolysis parameters such as door-tocomputerized tomographic (DTCT) and door-to-needle times improved significantly, although no significant difference was noted in the window period (Table 2). In patients receiving rtPA, the OTD times were 2 hours or less in 23.81%, 2-3 hours in 33.86%, and 3-4.5 hours in 42.33%, and the median OTD time was 91 minutes. Over the years, rates of early thrombolysis in 2 hours or less increased from 22% to 25% and those in 2-3 hours increased from 38.9% to 43.8%. The number of AIS patients who were thrombolysed increased over the years (from 18 in 2011 to 37 in 2015), with a peak (53 patients) in 2013. The median DTCT was 17 minutes, and in 70% patients, CT was carried out within 25 minutes of arrival. We observed that patients reporting early after symptom onset had short DTCT time intervals. The median window period of thrombolysis was 167 minutes and nearly half of the patient rtPA was started within 60 minutes of reporting deficit. IVT-related symptomatic intracranial hemorrhage was observed in 5 patients (2.65%), and thrombolysis-related in-hospital death occurred in 18 patients. Nearly 40% of the patients receiving rtPA achieved excellent outcome (mRS score 0-1) at 90 days, whereas up to 10% had complete recovery (mRS score 0). The trend of functional independence was nearly 60%, which recovered from marginal decline in 2012 (Fig 2). Excellent outcome trend improved in 2015 from 2014, although no significant variation was noted throughout the observed period.
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Table 3. Predictors of early arrival in all AIS patients (logistic regression: backward method) 95% CI for adjusted OR Predictors of early arrival (OTD ≤2 h)
Adjusted OR
Lower
Upper
P value
Female Reference category: male CAD or MI DM NIHSS score (baseline) Urban Reference category: semiurban Private vehicle Reference category: public vehicle In-hospital Reference category: public vehicle Constant
1.421
.972
2.078
.070
.628 .666 .973 1.589
.399 .437 .953 1.077
.987 1.016 .994 2.346
.044 .059 .011 .020
2.212
1.456
3.359
.0001
7.563
3.913
14.616
.0001
.379
.0001
Abbreviations: AIS, acute ischemic stroke; CAD, coronary artery disease; CI, confidence interval; DM, diabetes mellitus; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; OTD, onset to door.
Analyzing predictors of early arrival (using logistic regression), we observed that urban habitation and use of private vehicle saved time in bringing patients to the hospital (Table 3). Female patients tended to reach the hospital early but did not reach significance. In-hospital strokes (24 patients, −12.70%) saved transportation time and were predictive of early evaluation. Early thrombolysis (within 2 hours) did not predict a statistically significant good outcome.
Discussion Our study clearly shows a trend of increasing usage of IV rtPA among eligible stroke patients reaching the hospital within 4.5 hours of symptom onset, which nearly tripled over 5 years from 11.8% in 2011 to 31.5% in 2015. This registry-derived dataset study on temporal trends in IVT in AIS from a single center is possibly the first and largest to date from India. This substantial improvement is attributable in part to improving awareness in the general population, improvement in hospital systems, and continuous quality improvement measures undertaken at the local level (Table 2). A similar improved trend of IV tPA use has also been reported from other advanced stroke centers.7,8 The absolute number of patients receiving IV rtPA within 2 hours of symptom onset increased (from 7 to 15) over the years. With the expansion of window period for the use of IV rtPA from 3.0 to 4.5 hours, an additional 80 patients underwent thrombolysis. These results are consistent with prior studies signifying improving trend of thrombolysis worldwide.9,10 There was a shift in the population treated with IV tPA in terms of stroke severity with patients with milder strokes also undergoing IVT. Although community- and hospitalbased awareness programs contributed to early arrival
and good outcomes, the emerging concept of including milder and improving strokes for IVT due to their higher chance of being disabled if left untreated contributed to this improving trend in IVT.8,11 In contrast to developed countries, majority of our patients arrived in the ED using a private vehicle, the emergency medical service (EMS) being almost nonexistent. This finding also reflects the need to develop an effective EMS in developing countries, especially in India, which would be instrumental in reducing patient transfer times to stroke centers.12,13 Subanalysis of data shows a trend of increasing proportion of elderly patients receiving rtPA. This finding may be attributable to increasing confidence in the benefitto-harm ratio of rtPA in the elderly and the accumulation of evidence of efficacy of rtPA in advanced age.14 In our study group, 18.38% of all patients eligible for thrombolysis presented within 3 hours of the time last known well, the theoretical limit for rtPA use before 2009, and this result is comparable to other registries. In a prospective, multicenter-based registry of acute stroke patients in urban China, 25% of the patients arrived within 3 hours and 37% arrived within 6 hours after symptom onset.15 In the California Acute Stroke Pilot Registry, 23.5% arrived at the ED within 3 hours of symptom onset, whereas the Coverdell Registry reported that less than 18.5% of stroke patients arrived at the ED within 2 hours of symptom onset in 2005-2006.7,16 Other studies documented that 15%32% of patients presented within 3 hours of symptom onset.17-19 Female patients were found to report early (within 2 hours) compared to men, but the sex difference was insignificant. Other factors associated with early arrival were high NIHSS score, transport by own vehicle, urban population, and in-hospital stroke (Table 3). Nonavailability of the EMS in the developing world probably explains
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Table 4. Predictors for good outcome of AIS patients at 3 months 95% CI for OR Predictors for good outcome at 3 months (mRS score = 0-1) Male Transport facility Ambulance In-hospital Private NIHSS score (baseline) Hemorrhage OTN 2 h (1) Constant
Adjusted OR 1.753 4.466 1.418 2.310 .936 .283 1.876 .366
Lower
.878 Reference category : public transport 1.013 .286 .583 .895 .088 .919
Upper
P value
3.502
.112 .123 .048 .669 .233 .003 .035 .084 .219
19.690 7.023 9.154 .978 .914 3.832
Abbreviations: AIS, acute ischemic stroke; CI, confidence interval; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; OTN, onset to needle.
more use of private vehicles in medical emergency. We analyzed predictors of good outcome (mRS score 0-1) at 3 months and did not find any significant difference in sex (Table 4). Patients with low baseline NIHSS scores had better outcomes. Surprisingly, we did not observe a significant good outcome in patients receiving early rtPA (within 2 hours) compared to delayed thrombolysis (beyond 2 hours). A relatively higher (40%) rate of severe stroke in our cohort may explain this unanticipated finding. We observed steady and substantial improvements in hospital-based processes of care, as measured by timeliness of imaging and therapeutics and increased use of rtPA.20 The median time from door to brain imaging decreased by 16 minutes over the study period. In our cohort, 68.4% of patients were imaged within 25 minutes of hospital arrival, which compares favorably with rates of improvement reported in the literature and likely enabled greater numbers of patients to be treated with rtPA. The Coverdell registry reported a median time interval to initial imaging of ≈72 minutes for all patients and 42 minutes for the patients who arrived within 2 hours of symptom onset.7 Post-thrombolysis hemorrhage predicts a bad outcome, more common with symptomatic hemorrhage. Post-thrombolysis hemorrhage was seen in 13.23% of the patients, but symptomatic hemorrhage occurred in only 2.65% (5 patients), which is comparable to literature reports. In-hospital mortality was seen in 18 patients (9.5%), and at 90 days’ follow-up, 34 patients succumbed. This relatively high mortality was probably due to the high percentage (>40%) of severe stroke (NIHSS score >12) in our cohort. In addition, delay in transfer to stroke unit care due to limited resources and high patient burden in our setups may explain the high mortality. The number of patients receiving rtPA increased over the observed years, signifying improving stroke care and community awareness. However, the variation in the trend was not significant (Fig 2). Due to the high patient load in the ED and limited infrastructure, stroke unit care could
not be provided in all thrombolysed patients. The relative lack of EMS, delay in patient arrival and diagnosis, and high cost of rtPA are prominent challenges and also opportunities for requisite infrastructure development. The relative lack of EMS, delay in patient arrival and diagnosis, and high cost of rtPA are prominent challenges and critical issues in the management of AIS in developing countries. In conclusion, an improving trend indicates an increased awareness and acceptance of IVT in resourcelimited settings in developing countries. To facilitate this trend, a comprehensive program for community participation, promotion of stroke unit care, and government participation may be needed. Acknowledgments: We express our sincere gratitude to Ms. Suruchi Thakur for secretarial assistance, Mr. Mahendra Kumar Saini, Ms. Mohita Gupta, Mr. Divesh Munjal, and Ms. Hardeep Kaur for assisting in extracting data for the study. We thank the SITS registry for providing the stroke database of our institute.
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referral center in a developing country. Neurol India 2007;55:46-49. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282. Powers WJ, Derdeyn CP, Biller J, et al. 2015 AHA/ASA focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:3020-3035. George MG, Tong X, McGruder H, et al. Paul Coverdell National Acute Stroke Registry Surveillance: four states, 2005-2007. MMWR Surveill Summ 2009;58:1-23. Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:15811587. Demaerschalk BM, Bobrow BJ, Paulsen M. Development of a metropolitan matrix of primary stroke centers: the Phoenix experience. Stroke 2008;39:1246-1253. Grotta JC, Burgin WS, El-Mitwalli A, et al. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol 2001;58:2009-2013. Smith EE, Abdullah AR, Petkovska I, et al. Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke 2005;36:2497-2499.
12. Agyeman O, Nedeltchev K, Arnold M, et al. Time to admission in acute ischemic stroke and transient ischemic attack. Stroke 2006;37:963-966. 13. Center for Disease Control and Prevention (CDC). Prehospital and hospital delays after stroke onset—United States, 2005-2006. MMWR Morb Mortal Wkly Rep 2007;56:474-478. 14. Willey JZ, Petersen N, Dhamoon MS, et al. Safety of thrombolysis in patients over the age of 80. Neurologist 2012;18:99-101. 15. Jin H, Zhu S, Wei JW, et al. Factors associated with prehospital delays in the presentation of acute stroke in urban China. Stroke 2012;43:362-370. 16. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology 2005;64:654-659. 17. 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. 18. Fink JN, Selim MH, Kumar S, et al. Why are stroke patients excluded from tPA therapy? An analysis of patient eligibility. Neurology 2001;57:1739-1740. 19. Kleindorfer D, Kissela B, Schneider A, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke 2004;35:e27-e29. 20. Ekundayo OJ, Saver JL, Fonarow GC, et al. Patterns of emergency medical services use and its association with timely stroke treatment: findings from Get with the Guidelines–Stroke. Circ Cardiovasc Qual Outcomes 2013;6:262-269.
Temporal Trends in Intravenous Thrombolysis in Acute Ischemic Stroke: Experience from a Tertiary Care Center in India Dheeraj Khurana, MD, DM,* Biplab Das, DM,* Ashok Kumar, MD,* Amith Kumar S., MD,* Niranjan Khandelwal, MD,† Vivek Lal, DM,* and Sudesh Prabhakar, DM*
Background: Acute ischemic stroke (AIS) is a time-dependent treatable cause of morbidity and mortality. Despite the increasing stroke incidence in developing countries, parallel increasing stroke thrombolysis rates have not been documented. Aim: This study aims to determine trends in patient characteristics and rates of recombinant tissue plasminogen activator (rtPA) use in AIS patients in a tertiary care center in northern India. Methods: All AIS patients presenting within 8 hours of symptoms onset from January 2011 to December 2015 were enrolled and analyzed. Results: A total of 867 AIS patients presented within 8 hours of symptoms onset. Out of 593 eligible patients, 189 (31.87%) underwent intravenous thrombolysis (IVT) with rtPA within 4.5 hours of the window period. Patients (undergoing) IVT had onset-to-door times of 2 hours or less (23.81%), 2-3 hours (33.86%), and 3.0-4.5 hours (42.33%). IVT rates in 2 hours or less of symptom onset increased from 22% to 25% and IVT rates in 2-3 hours increased from 38.9% to 43.8%. Door-tocomputerized tomographic time (median 27 versus 11 minutes, P = .0001) and doorto-needle time (median 83 versus 67 minutes, P = .011) improved, with a significant improvement of computerized tomography imaging time within 25 minutes of arrival (from 50% to 78.4%, P = .014). Post-IVT symptomatic hemorrhage was noted in 5 patients (2.65%). The median National Institutes of Health Stroke Scale score at presentation was 11, whereas a favorable modified Rankin Scale score (0-1) at 3 months was seen in 39.68%. Conclusions: Encouraging trends in IVT over the years may be indicative of increasing community awareness of stroke and improving quality of stroke care in developing countries such as India. Key Words: Stroke—intravenous thrombolysis—rtPA—trends—developing countries. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India; and †Department of Radiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Received November 8, 2016; revision received January 17, 2017; accepted January 20, 2017. D.K. and B.D. have equal first authorship. Address correspondence to Dheeraj Khurana, MD, DM, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.01.019
Eligibility for acute ischemic stroke (AIS) interventions depends on the time from symptom onset to hospital arrival. Only a minority of patients arrived early enough to be considered for acute therapy, and most studies describe experiences of specific centers or regional networks over a limited time period.1 Many patients without documented contraindications still do not receive intravenous (IV) recombinant tissue plasminogen activator (rtPA), despite being currently the only approved medical treatment for patients with AIS within 4.5 hours of stroke onset.1,2 Worldwide, professional
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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societies, different state and government agencies, and national patient support organizations are making efforts to increase rtPA use in eligible patients.3 Although studies in developed countries have demonstrated significant improvement in trends in intravenous thrombolysis (IVT), there are limited data from developing countries and the Indian subcontinent.4 The present study highlights trends in IV rtPA use over 5 years in a large tertiary care hospital in North India.
Methods Case Definition The stroke onset times were recorded as the time the patient was last known to be well and the time that symptom onset was discovered; approximate times were not allowed. The onset-to-door (OTD) time was defined as the time the patient arrived in the emergency department (ED) minus the stroke onset time. The onset-toneedle time (OTN) was equivalent to the window period, whereas the door-to-needle time was the time taken to start IVT after reaching the hospital. Thrombolysisinduced symptomatic intracranial hemorrhage was defined as a type 2 parenchymal hemorrhage with deterioration with a National Institutes of Health Stroke Scale (NIHSS) score of 4 points or higher or death, within 36 hours of thrombolysis (as per Safe Implementation of Thrombolysis in Stroke-Monitoring Study [SITS-MOST]).5
Patient Population The primary objective of the study was to evaluate the changes in the patterns of use of IVT over a 5-year period from January 2011 to December 2015. We report data of all AIS patients who were treated with IVT within 4.5 hours of symptom onset. Data were derived from our hospital stroke registry and the Safe Implementation of Treatments in Stroke (SITS)—India registry, where our hospital data were also registered. Our stroke team comprised neurology and neuroradiology physicians, fellows, and stroke nurses and had been in place before 2011. Acute stroke notification of the stroke team members was provided by emergency mobile notification. Stroke team members rotate on “first call” and are available 24 × 7. A regular education program of residents and nurses is carried out to train them on early and accurate recognition of acute stroke patients and to institute an acute stroke management pathway that includes immediate notification of our stroke team and early evaluation of patient and assessment of the usual exclusions to rtPA. In all eligible patients of thrombolysis, baseline blood pressure and blood sugar levels were determined and rapid coagulogram (point of care) was carried out before rtPA bolus dose. Data were recorded in a brief acute stroke card listing patients’ demographics, stroke type, intervals, and other critical
Figure 1. Recruitment profile of an acute ischemic stroke patient and thrombolysis window period. Abbreviation: IVT, intravenous thrombolysis.
information pertaining to thrombolysis. The platelet counts were immediately ordered, but IVT was started while the report was awaited, with instructions to stop IVT in case of low platelet counts. All patients were closely monitored closely in the post-thrombolytic period as per guidelines.6 Patients receiving IVT were divided into the following groups: within (1) 2 hours, (2) 2-3 hours, and (3) 3.0-4.5 hours. Patients treated after 4.5 hours of the window period were not included in the analysis. A total of 196 patients underwent IVT during this period; 7 patients were excluded as IVT was carried out after 4.5 hours (posterior circulation stroke) (Fig 1).
Imaging All patients underwent a cranial CT scan with CT angiography. All patients underwent a follow-up CT scan at 24 hours of IVT. We have not included the CT angiographic data in the present study.
Statistical Analysis For each of the 3 patient groups, demographics and clinical variables were analyzed (Table 1). Temporal trends were explored for the groups treated with IV rtPA within 4.5 hours of onset by calendar year from 2011 through December 2015 (Table 2).Yearly trends over time in OTN were tabulated according to the following categories: OTN time of 2 hours, OTN time of 2-3 hours, and OTN time
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Table 1. Baseline characteristics and thrombolysis-related parameters
Patients characteristics
All AIS patients within 8 h (n = 867)
All IVT (OTN ≤4.5 h) (n = 189)
IVT (OTN ≤2 h) (n = 45)
IVT (OTN 2-3 h) (n = 64)
IVT (OTN 3.0-4.5 h) (n = 80)
Demographics Age (years), median (IQR), n (%)
60 (50.0-70.5)
60 (49-72)
60 (47.5-65.5)
61 (50.0-71.75)
104 (12) 359 (41.4) 336 (38.8) 68 (7.8)
22 (11.6) 75 (39.7) 78 (41.3) 14 (7.4)
4 (8.9) 19 (42.2) 19 (42.2) 3 (6.7)
7 (10.9) 24 (37.5) 28 (43.8) 5 (7.8)
59.5 (49.25-73.75) P = .908 11 (13.8) 32 (40) 31 (38.8) 6 (7.5) P = .988
Sex, n (%) Men Women
574 (66.2) 293 (33.8)
124 (65.6) 65 (34.4)
30 (66.7) 15 (33.3)
39 (60.9) 25 (39.1)
55 (68.8) 25 (31.2) P = .609
Transport facility, n (%) Ambulance Own vehicle Public vehicle In-hospital
201 (23.2) 430 (49.6) 148 (17.1) 88 (10.1)
42 (22.2) 109 (57.7) 14 (7.4) 24 (12.7)
5 (11.1) 26 (57.8) 2 (4.4) 12 (26.7)
8 (12.5) 43 (67.2) 6 (9.4) 7 (10.9)
29 (36.2) 40 (50.1) 6 (7.5) 5 (6.2) P = .001
Occupation, n (%) Government employee or retired Private employee or laborer Unemployed or housewife
268 (30.9) 157 (18.1) 442 (51)
58 (30.7) 37 (19.6) 94 (49.7)
13 (28.9) 7 (15.6) 25 (55.6)
17 (26.6) 13 (20.3) 34 (53.1)
28 (35) 17 (21.2) 35 (43.8) P = .663
Habitat, n (%) Rural Semiurban Urban
174 (20.1) 104 (12) 589 (67.9)
38 (20.1) 24 (12.7) 127 (67.2)
9 (20) 7 (15.6) 29 (64.4)
13 (20.3) 6 (9.4) 45 (70.3)
Atrial fibrillation, n (%)
156 (18)
36 (19.0)
10 (22.2)
13 (20.3)
Hypertension, n (%)
468 (54)
104 (55.0)
23 (51.1)
39 (60.9)
CAD or previous MI, n (%)
189 (21.8)
35 (18.5)
5 (11.1)
12 (18.8)
Diabetes mellitus, n (%)
208 (24)
45 (23.8)
8 (17.8)
17 (26.6)
Smoking, n (%)
225 (25.9)
46 (24.3)
15 (33.3)
8 (12.5)
Prior CVA or TIA, n (%)
131 (15.1)
30 (15.9)
6 (13.3)
8 (12.5)
11 (5-20)
11 (6-18)
11 (6.5-17)
12 (6-17)
16 (20) 11 (13.8) 53 (66.2) P = .902 13 (16.2) P = .682 42 (52.2) P = .499 18 (22.5) P = .290 20 (25) P = .540 23 (28.8) P = .021 16 (20) P = .410 11 (7.25-20) P = .630
Baseline NIHSS levels, n (%) 0-7 8-12 13-25 Higher than 25
276 (31.8) 202 (23.4) 322 (37.1) 67 (7.7)
58 (30.7) 48 (25.4) 70 (37.0) 13 (6.9)
14 (31.1) 12 (26.7) 18 (40) 1 (2.2)
24 (37.5) 12 (18.8) 24 (37.5) 4 (6.2)
OTD (min), median (IQR)
168 (86-295)
91 (55-143.5)
35 (15-60)
DTCT time (min), median (IQR)
NA
17 (10-30)
15 (9-25)
15 (8-28)
DTCT time (≤25 min)
NA
133 (70.4%)
37 (82.2%)
46 (71.9%)
OTN (min), median (IQR)
NA
165 (127.5-225)
100 (78-110)
150 (135-165)
DTN (min), median (IQR)
NA
63 (48.5-85)
55 (41-65)
DTN (≤60 min)
NA
89 (47.1%)
31 (68.9%)
40 or under 41-60 61-80 Over 80
Baseline NIHSS score, median (IQR)
80.5 (62-95.75)
69.5 (50.25-88.75) 25 (39.1%)
20 (25) 24 (30) 28 (35) 8 (10) P = .397 154 (116.25-179) P = .0001 22 (10-36) P = .051 50 (62.5%) P = .065 230 (210-250) P = .0001 66 (48.5-103) P = .002 33 (41.2%) P = .003
Abbreviations: AIS, acute ischemic stroke; CAD, coronary artery disease; CVA, cerebrovascular accident; DTCT, door to computerized tomographic; DTN, door to needle; IQR, interquartile range; IVT, intravenous thrombolysis; MI, myocardial infarction; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale; OTD, onset to door; OTN, onset to needle; TIA, transient ischemic attack.
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Table 2. Trend of different thrombolysis-related parameters from January 2011 to December 2015
Hemorrhage SICH IVT-related death (in-hospital)
2011
2012
2013
2014
2015
P value
189 60 (49-72) 124/65 91 (55.0-143.5) 17 (10-30) 63 (48.5-85.0) 165 (1275-225) 104 45 36 30 35 46 11 (6-18) 75
18 59.5 (46.5-70.5) 14/4 83 (52.5-101.25) 27 (15-35) 82.5 (58.75-116.25) 167.5 (123.75-246.25) 9 (50) 2 (11.1) 3 (16.7) 1 (5.6) 2 (11.1) 4 (22.2) 13 (5-23) 8 (44.4)
33 65 (52-75.5) 28/5 81 (45.0-147.5) 25 (20.5-39.0) 78 (58-105) 185 (137.5-235.0) 21 (63.3) 8 (24.2) 5 (15.2) 6 (18.2) 8 (24.2) 8 (24.2) 15 (10-23) 14 (42.4)
53 65 (46-75) 30/23 92 (57.5-151) 18 (10.0-29.5) 56 (47-80) 150 (117.5-220.0) 32 (60.4) 13 (24.5) 8 (15.1) 5 (9.4) 11 (20.8) 9 (17) 11 (6-17) 23 (43.4)
48 60 (50-71.75) 30/18 91.5 (50.75-127) 11 (5-17) 60 (45.0-78.75) 152.5 (121.25-202.5) 23 (47.9) 15 (31.3) 12 (25) 11 (22.9) 8 (16.7) 14 (29.2) 11 (6-16) 17 (35.4)
37 58 (45-63.5) 22/15 95 (73-160) 11 (8.0-23.5) 67 (47.5-80.0) 195 (135-230) 19 (51.4) 7 (18.9) 8 (21.6) 7 (18.9) 6 (16.2) 11 (29.7) 10 (5.0-16.5) 13 (43.3) N = 30 2 (5.4) 2 3
.0001 .169 .053 F .581 .0001 .011 .238 .563 .500 F .726 F .270 F .810 F .586 F .121 .921
25 5 18
2 (11.1) 0 1
5 (15.2) 0 2
8 (15.1) 0 6
8 (16.7) 3 6
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Number of patients Age (years), median (IQR) Sex (M/F) OTD (min), median (IQR) DTCT (min), median (IQR) DTN (min), median (IQR) OTN (min), median (IQR) HTN DM AF Previous CVA or TIA CAD or MI Smoking Baseline NIHSS score, median (IQR) mRS score (0-1)
All IVT
.569 F
Abbreviations: AF, arterial fibrillation; CAD, coronary artery disease; CVA, cerebrovascular accident; DM, diabetes mellitus; DTCT, door to computerized tomographic; DTN, door to needle; F, female; HTN, hypertension; IQR, interquartile range; IVT, intravenous thrombolysis; M, male; MI, myocardial infarction; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OTD, onset to door; OTN, onset to needle; SICH, symptomatic intracerebral hemorrhage; TIA, transient ischemic attack. D. KHURANA ET AL.
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Figure 2. Trend of outcome (mRS score) of patients receiving intravenous recombinant tissue plasminogen activator within 4.5 hours of ischemic stroke at 90 days. Abbreviation: mRS, modified Rankin Scale.
of 3.0-4.5 hours. Continuous variables were compared by Kruskal–Wallis test. Categorical variables were compared by χ2 test. Predictors of early arrival (≤2 hours) and good outcome (modified Rankin Scale [mRS] score 0-1) were identified using multivariable analysis (Tables 3, 4).
Results From January 2011 to December 2015, 867 patients of AIS who presented within 8 hours of stroke were recruited in the study and 189 (31.87%) patients underwent IVT out of 593 eligible candidates (presenting within 4.5 hours of window period). Common causes for exclusion were financial constraint, high cost of rtPA, and negative consent. Age and sex distributions were similar across the cohorts (Table 1). However, compared to female patients, twice the number of male patients underwent thrombolysis. Seven percent of the patients were over 80 years of age, whereas no significant preferred age group was observed in patients who underwent thrombolysis. Ambulance was used in 23.2% to bring patients to the hospital, whereas 22.2% of rtPA-treated patients used an ambulance. Most patients (57.7%) used a private vehicle to reach the hospital. Majority of the thrombolysed patients were from urban areas, but no major difference was noted in early reporting to hospital compared to patients from rural areas. Atrial fibrillation was seen in ~20% patients. There was no significant difference in the initial median NIHSS score in the rtPA-eligible and rtPAtreated groups compared to all AIS patients. More than 40% of the patients had a severe stroke (NIHSS score >12), whereas 6.9% had an NIHSS score higher than 25. Subanalysis of data showed that patients with severe strokes tended to report early.
In univariate analysis, rtPA use changed over time across most patient characteristics measured, with a pattern of expanding the treated population into a broader range (Table 1). The number of patients receiving rtPA aged over 80 years increased over the years. There were significant improvements in the trend of rtPA use in women (from 22.2% to 40.54%, P = .031). Over the years, the trend in effective thrombolysis parameters such as door-tocomputerized tomographic (DTCT) and door-to-needle times improved significantly, although no significant difference was noted in the window period (Table 2). In patients receiving rtPA, the OTD times were 2 hours or less in 23.81%, 2-3 hours in 33.86%, and 3-4.5 hours in 42.33%, and the median OTD time was 91 minutes. Over the years, rates of early thrombolysis in 2 hours or less increased from 22% to 25% and those in 2-3 hours increased from 38.9% to 43.8%. The number of AIS patients who were thrombolysed increased over the years (from 18 in 2011 to 37 in 2015), with a peak (53 patients) in 2013. The median DTCT was 17 minutes, and in 70% patients, CT was carried out within 25 minutes of arrival. We observed that patients reporting early after symptom onset had short DTCT time intervals. The median window period of thrombolysis was 167 minutes and nearly half of the patient rtPA was started within 60 minutes of reporting deficit. IVT-related symptomatic intracranial hemorrhage was observed in 5 patients (2.65%), and thrombolysis-related in-hospital death occurred in 18 patients. Nearly 40% of the patients receiving rtPA achieved excellent outcome (mRS score 0-1) at 90 days, whereas up to 10% had complete recovery (mRS score 0). The trend of functional independence was nearly 60%, which recovered from marginal decline in 2012 (Fig 2). Excellent outcome trend improved in 2015 from 2014, although no significant variation was noted throughout the observed period.
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Table 3. Predictors of early arrival in all AIS patients (logistic regression: backward method) 95% CI for adjusted OR Predictors of early arrival (OTD ≤2 h)
Adjusted OR
Lower
Upper
P value
Female Reference category: male CAD or MI DM NIHSS score (baseline) Urban Reference category: semiurban Private vehicle Reference category: public vehicle In-hospital Reference category: public vehicle Constant
1.421
.972
2.078
.070
.628 .666 .973 1.589
.399 .437 .953 1.077
.987 1.016 .994 2.346
.044 .059 .011 .020
2.212
1.456
3.359
.0001
7.563
3.913
14.616
.0001
.379
.0001
Abbreviations: AIS, acute ischemic stroke; CAD, coronary artery disease; CI, confidence interval; DM, diabetes mellitus; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; OTD, onset to door.
Analyzing predictors of early arrival (using logistic regression), we observed that urban habitation and use of private vehicle saved time in bringing patients to the hospital (Table 3). Female patients tended to reach the hospital early but did not reach significance. In-hospital strokes (24 patients, −12.70%) saved transportation time and were predictive of early evaluation. Early thrombolysis (within 2 hours) did not predict a statistically significant good outcome.
Discussion Our study clearly shows a trend of increasing usage of IV rtPA among eligible stroke patients reaching the hospital within 4.5 hours of symptom onset, which nearly tripled over 5 years from 11.8% in 2011 to 31.5% in 2015. This registry-derived dataset study on temporal trends in IVT in AIS from a single center is possibly the first and largest to date from India. This substantial improvement is attributable in part to improving awareness in the general population, improvement in hospital systems, and continuous quality improvement measures undertaken at the local level (Table 2). A similar improved trend of IV tPA use has also been reported from other advanced stroke centers.7,8 The absolute number of patients receiving IV rtPA within 2 hours of symptom onset increased (from 7 to 15) over the years. With the expansion of window period for the use of IV rtPA from 3.0 to 4.5 hours, an additional 80 patients underwent thrombolysis. These results are consistent with prior studies signifying improving trend of thrombolysis worldwide.9,10 There was a shift in the population treated with IV tPA in terms of stroke severity with patients with milder strokes also undergoing IVT. Although community- and hospitalbased awareness programs contributed to early arrival
and good outcomes, the emerging concept of including milder and improving strokes for IVT due to their higher chance of being disabled if left untreated contributed to this improving trend in IVT.8,11 In contrast to developed countries, majority of our patients arrived in the ED using a private vehicle, the emergency medical service (EMS) being almost nonexistent. This finding also reflects the need to develop an effective EMS in developing countries, especially in India, which would be instrumental in reducing patient transfer times to stroke centers.12,13 Subanalysis of data shows a trend of increasing proportion of elderly patients receiving rtPA. This finding may be attributable to increasing confidence in the benefitto-harm ratio of rtPA in the elderly and the accumulation of evidence of efficacy of rtPA in advanced age.14 In our study group, 18.38% of all patients eligible for thrombolysis presented within 3 hours of the time last known well, the theoretical limit for rtPA use before 2009, and this result is comparable to other registries. In a prospective, multicenter-based registry of acute stroke patients in urban China, 25% of the patients arrived within 3 hours and 37% arrived within 6 hours after symptom onset.15 In the California Acute Stroke Pilot Registry, 23.5% arrived at the ED within 3 hours of symptom onset, whereas the Coverdell Registry reported that less than 18.5% of stroke patients arrived at the ED within 2 hours of symptom onset in 2005-2006.7,16 Other studies documented that 15%32% of patients presented within 3 hours of symptom onset.17-19 Female patients were found to report early (within 2 hours) compared to men, but the sex difference was insignificant. Other factors associated with early arrival were high NIHSS score, transport by own vehicle, urban population, and in-hospital stroke (Table 3). Nonavailability of the EMS in the developing world probably explains
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Table 4. Predictors for good outcome of AIS patients at 3 months 95% CI for OR Predictors for good outcome at 3 months (mRS score = 0-1) Male Transport facility Ambulance In-hospital Private NIHSS score (baseline) Hemorrhage OTN 2 h (1) Constant
Adjusted OR 1.753 4.466 1.418 2.310 .936 .283 1.876 .366
Lower
.878 Reference category : public transport 1.013 .286 .583 .895 .088 .919
Upper
P value
3.502
.112 .123 .048 .669 .233 .003 .035 .084 .219
19.690 7.023 9.154 .978 .914 3.832
Abbreviations: AIS, acute ischemic stroke; CI, confidence interval; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; OTN, onset to needle.
more use of private vehicles in medical emergency. We analyzed predictors of good outcome (mRS score 0-1) at 3 months and did not find any significant difference in sex (Table 4). Patients with low baseline NIHSS scores had better outcomes. Surprisingly, we did not observe a significant good outcome in patients receiving early rtPA (within 2 hours) compared to delayed thrombolysis (beyond 2 hours). A relatively higher (40%) rate of severe stroke in our cohort may explain this unanticipated finding. We observed steady and substantial improvements in hospital-based processes of care, as measured by timeliness of imaging and therapeutics and increased use of rtPA.20 The median time from door to brain imaging decreased by 16 minutes over the study period. In our cohort, 68.4% of patients were imaged within 25 minutes of hospital arrival, which compares favorably with rates of improvement reported in the literature and likely enabled greater numbers of patients to be treated with rtPA. The Coverdell registry reported a median time interval to initial imaging of ≈72 minutes for all patients and 42 minutes for the patients who arrived within 2 hours of symptom onset.7 Post-thrombolysis hemorrhage predicts a bad outcome, more common with symptomatic hemorrhage. Post-thrombolysis hemorrhage was seen in 13.23% of the patients, but symptomatic hemorrhage occurred in only 2.65% (5 patients), which is comparable to literature reports. In-hospital mortality was seen in 18 patients (9.5%), and at 90 days’ follow-up, 34 patients succumbed. This relatively high mortality was probably due to the high percentage (>40%) of severe stroke (NIHSS score >12) in our cohort. In addition, delay in transfer to stroke unit care due to limited resources and high patient burden in our setups may explain the high mortality. The number of patients receiving rtPA increased over the observed years, signifying improving stroke care and community awareness. However, the variation in the trend was not significant (Fig 2). Due to the high patient load in the ED and limited infrastructure, stroke unit care could
not be provided in all thrombolysed patients. The relative lack of EMS, delay in patient arrival and diagnosis, and high cost of rtPA are prominent challenges and also opportunities for requisite infrastructure development. The relative lack of EMS, delay in patient arrival and diagnosis, and high cost of rtPA are prominent challenges and critical issues in the management of AIS in developing countries. In conclusion, an improving trend indicates an increased awareness and acceptance of IVT in resourcelimited settings in developing countries. To facilitate this trend, a comprehensive program for community participation, promotion of stroke unit care, and government participation may be needed. Acknowledgments: We express our sincere gratitude to Ms. Suruchi Thakur for secretarial assistance, Mr. Mahendra Kumar Saini, Ms. Mohita Gupta, Mr. Divesh Munjal, and Ms. Hardeep Kaur for assisting in extracting data for the study. We thank the SITS registry for providing the stroke database of our institute.
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