Gaps and Hurdles Deter against Following Stroke Guidelines for Thrombolytic Therapy in Iran: Exploring the Problem Karim Nikkhah, MD,*1 Abolfazl Avan, MD,*†1 Ali Shoeibi, MD,* Amir Azarpazhooh, DDS, PhD,‡xk1 Kavian Ghandehari, MD,* Christian Foerch, MD,{ Gustavo Saposnik, MD,# Payam Sasannejad, MD,* Veda Vakili, MD,** Parvaneh Layegh, MD,†† Mohammad Taghi Farzadfard, MD,* Reza Bavarsad Shahripour, MD,‡‡ Mohammad Reza Hosseini, MD,* and Mahmoud Reza Azarpazhooh, MD*
Background: Insufficient information is available on the barriers that explain low rates of thrombolytic therapy for acute ischemic stroke (AIS) in developing countries compared with rates in developed societies. By the present study, we aimed to assess the implementation of thrombolytic therapy in the northeast of Iran to explore the gaps and hurdles against thrombolysis as the generally accepted treatment for AIS. Methods: In a 1-year cohort study among AIS patients admitted to the second largest tertiary neurologic referral center in Iran, those who met the prespecified selection criteria were treated with intravenous recombinant tissue plasminogen activator (rtPA). Results: Among 1,144 patients admitted with AIS, only 14 (1.2%) were treated with rtPA. The mean onset-to-needle and door-to-needle times were 172 and 58 minutes, respectively; 980 (85.6%) patients were initially excluded from the study because of late arrival. Additionally, 60 patients in total were omitted because of either their high age (3.7%) or passing the gold standard time limit for rtPA therapy after preliminary evaluations (1.6%), and 90 more patients (7.9%) were considered not suitable for thrombolysis because of the severity of the symptoms or the higher risk of bleeding on rtPA. Conclusions: Access to thrombolytic therapy for AIS in Iran is less than in most developed countries but comparable with other developing countries. Awareness campaigns are needed to minimize barriers and improve access to thrombolysis and specialized stroke care in Iran. Key Words: Stroke— thrombolysis—developing countries—stroke facilities—cohort study—treatment. Ó 2015 by National Stroke Association
From the *Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; †Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; ‡Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; xClinical Epidemiology Program, Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; kToronto Health Economics and Technology Assessment Collaborative, University of Toronto, Toronto, Ontario, Canada; {Department of Neurology, Goethe-University, Frankfurt am Main, Germany; #The Division of Neurology, Department of Medicine, Stroke Outcomes Research Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; **Department of Community and Preventive Medicine, School of Medicine, Mashhad University of Medical
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Sciences, Mashhad, Iran; ††Department of Radiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; and ‡‡Comprehensive Stroke Center, Department of Neurology, University of Alabama, Birmingham, Alabama. Received July 10, 2014; revision received September 4, 2014; accepted September 7, 2014. Address correspondence to Mahmoud Reza Azarpazhooh, MD, Department of Neurology, Ghaem Hospital, Taghi Abad Square, Mashhad, 91766-99199, Iran. E-mail: [email protected]. 1 These authors contributed equally to this work. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.012
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 2 (February), 2015: pp 408-415
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Introduction Stroke is the leading cause of functional impairment1 and the second most common cause of mortality in developed and developing countries.2 Many survivors had debilitating disabilities and low quality of life, along with high financial burdens of lifelong care and rehabilitation.3 An estimated 2%-5% of the total health care expenditures in western countries are dedicated to the diagnosis and treatment of stroke.4,5 Because of geographic variations, controversial results, and a lack of well-designed community-based studies, the incidence rates and outcome of stroke are not well characterized in Middle East countries. Our recent large population-based study showed that in Iran, compared with developed countries, the incidence of stroke was higher and its occurrence was about 1 decade earlier.6 Considering these findings, the burden of stroke in Iran appears to be enormous and has to be considered as a public health priority. Although primary prevention is definitely the best way to control the rate of stroke, this devastating situation can also be combated by assessing the suitability of thrombolytic therapy as the available effective treatment for acute ischemic stroke (AIS). Early administration of intravenous recombinant tissue plasminogen activator (rtPA) proved to be effective in reducing mortality, improving neurologic outcomes, and limiting lesion growth.7,8 The earlier the treatment is administered, the more effective it might be and the better the prognosis for the patients.9 rtPA has been found to be a cost-effective treatment for AIS in developed countries.10 Despite the high rate of stroke in Iran, rtPA for AIS has rarely been used in daily practice.6 The possible consequences and cost of rtPA therapy, along with its sparse medication distribution and insufficient prehospital and posthospital infrastructures, deter against its widespread use and sometimes make it ‘‘fearsome.’’ In this study, we aimed to assess the feasibility, but not the efficacy or outcome, of rtPA therapy to find and overcome barriers against its routine administration among patients with AIS in Mashhad, the second largest city in Iran.
Methods Design The investigation is a cohort study, approved by the Research Ethics Board, Mashhad University of Medical Sciences (no. 89728). Written informed consent was provided by patients or their next of kin before enrolling into the study.
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more than 2.5 million citizens, is the second most populated city of Iran. During a 1-year study period (from September 2011 to September 2012), all patients with AIS who met our inclusion criteria for rtPA therapy, which were mainly according to the 2010 American Heart Association/American Stroke Association stroke guideline11 and the Alberta Stroke Program Early Computed Tomography Score,12 were enrolled in the study (Fig 1). However, some criteria were modified according to the barriers and access to rtPA, particularly regarding the cost. Patients older than 75 years and those who passed the 3-hour window time for thrombolytic therapy after evaluation were excluded from the study mainly because of physicians’ concerns for rtPA complications. Demographic characteristics and medical and laboratory histories were recorded for each individual patient. Furthermore, we recorded the mean time from symptom onset to admission (onset to door), admission to computed tomography (CT) (door to CT scan), admission to treatment (door to needle), and symptom onset to rtPA treatment (onset to needle).
Treatment Protocol Eligible patients were treated with one 50-mg vial of rtPA; 10% of the vial (ie, 5 mg) was slowly infused within 1 minute, and the remaining was infused within the following 60 minutes. Considering the lack of 10-mg vials, in particular, and the relatively high out-of-pocket cost in Iran, we used a lower dosage of rtPA, comparable with the effective .6 mg/kg dose as reported from Japan.13
Outcomes The primary outcomes were the rate of rtPA administration during the study period. The National Institutes of Health Stroke Scale (NIHSS) was used to quantify the level of impairment caused by stroke, and the modified Rankin Scale (mRS) was used to quantify the degree of patients’ improvements in doing their daily activities.7 We considered an mRS score of 0-1 at 3 months after treatment and also improvement by more than 4 in NIHSS at 2 hours and 3 months after rtPA as favorable outcomes. We also measured safety outcome, defined as mortality, brain edema, cardiac arrhythmia, orolingual angioedema, and asymptomatic intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage (SICH) because of thrombolytic therapy. Based on the Canadian Stroke Network definition,14 SICH was defined as any ICH resulting in neurologic deficit during the first 36 hours of rtPA treatment. Furthermore, the length of hospital stay was also recorded for each patient.
Population The study was performed at the stroke unit of Ghaem Hospital, a tertiary neurologic referral center in Mashhad in the northeast of Iran. Mashhad, with a population of
Data Analysis SPSS 11.5 (SPSS Inc., Chicago, IL) was used for all statistical analyses. Standard descriptive statistics were
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Figure 1. Target population for rtPA treatment in acute ischemic stroke patients based on the inclusion and exclusion criteria. ‘‘*,’’ 22 of 164 cases had more than 1 exclusion criterion, including 12 cases overlapped with the age limit, 4 also passed 3-hour window time after evaluations, and 6 in 13 other criteria. Abbreviations: ASPECT, Alberta Stroke Program Early CT Score; CT, computed tomography; CVA, cerebrovascular ischemic attack; DBS, diastolic blood pressure; GIB, gastrointestinal bleeding; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.
applied to describe the pattern of the data. A chi-square test was used to examine the significance of the association between categorical data. The data were checked with a Kolmogorov–Smirnov test for normal distribution. For continuous data, t test and Mann–Whitney U test were used as indicated. A 2-tailed P value of less than .05 was considered to be significant.
Results During the study period, 1,144 patients with AIS were admitted, of whom a small proportion (n 5 164 patients, 14.3%) was admitted within the first 3 hours of symptom onset (Fig 1). A total of 22 patients of 164 had more than 1 exclusion criterion. Finally, 14 patients (1.2%; 9 men and 5 women) received rtPA therapy.
The mean baseline NIHSS score of the 14 treated patients was 14.1 6 2.7 (range 9-18) before rtPA therapy. After the treatment, this value was reduced to 5.8 6 4.3 (range 0-18) after 2 hours (ie, a 59% reduction) and to 3.4 6 2.9 (range 0-18) after 3 months (ie, a 75.7% reduction; P , .001). The NIHSS scores were significantly improved by more than 75% in more than half of the patients (8 of 14) and by more than 50% in 85.7% of the patients (12 of 14). Three patients reached the NIHSS score of 0 at 3 months after the treatment. Half of the participants (7 of 14) reported favorable outcomes (mRS scoring 0-1) 3 months after the treatment, whereas 2 patients had an mRS score of 2 and the other 5 patients had an mRS score of 3 or more. All 14 patients survived at 3 months after the treatment. The mean age of these 14 patients was 54.9 6 11.3 years (range 35-75), with no significant difference between
BARRIERS AGAINST THROMBOLYTIC THERAPY IN IRAN
genders (P 5 .53). The mean onset-to-door time and to be visited by the on-call neurologist were 113.2 6 21.3 (range 60-135) and 19.3 6 4.3 (range 15-30) minutes, respectively. The mean door-to-CT scan time was 14.3 6 5.1 minutes (range 10-25). The mean onset-to-needle and door-toneedle times were 172.1 6 13.1 (range 135-180) and 57.6 6 8.2 (range 48-66) minutes, respectively. The 2 most common complications of rtPA treatment were brain edema (4 of 14) and bradycardia (4 of 14). Asymptomatic ICH happened in 2 patients; 1 was accompanied by intraventricular hemorrhage. We did not observe SICH nor any orolingual angioedema or other hemorrhagic events (including gastrointestinal and urologic bleeding and dermal purpura or ecchymosis) during the study period.
Discussion Early administration of rtPA has been shown to significantly improve clinical outcomes and decrease mortality after AIS.7,15 Although the majority of the stroke burden worldwide occurs in developing countries with a 10year earlier stroke onset,6,16 a ‘‘fearful’’ attitude exists in such countries regarding the potential complications of rtPA. In the present study, only 14 (1.2%) patients with AIS were treated with rtPA during the 1-year study period. A recent systematic review17 assessed the global use of rtPA for AIS among 214 countries and found that only 54 (25%) of these countries reported its administration, ranging from as low as 3% (1 of 36) of low-income, to 13% (7 of 54) of lower middle-income, to 28% (15 of 54) of upper middle-income, and to 44% (31 of 70) of highincome countries.17 In comparison, access to rtPA in Iran is lower than in most of the developed countries1825 but comparable with other developing countries26-32 (Fig 2). The barriers of timely administration of rtPA in developing countries include limited resources, prehospital delay, sparse numbers of stroke units,16,33 poor stroke awareness in the general population,33 lack of general knowledge and professional education,33,34 the high cost of rtPA, lack of insurance coverage, low socioeconomic status of patients,16,33 and physician reluctance and concerns about the benefits compared with its serious side effects, especially bleeding.34-36 Time from symptom onset to hospital arrival is the most important factor in choosing the right patients for thrombolytic therapy.37 In our study, 85.7% of our admitted patients were excluded because of late arrival to the hospital (after 3 hours; Fig 3). In Canada and the United States, about 75% of AIS patients presented to hospital after 3 hours of symptom onset.35,37 Hospital arrival in busy urban settings in developing countries can be significantly delayed because of road traffic. To address this problem in our setting, in collaboration with Mashhad Traffic and Transportation Organization, we
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designed an online Emergency Medical Services Traffic System to control the traffic lights and direct the ambulance driver to the quickest least congested pathway route to the hospital. With better education and improved infrastructural facilities, such as rapid Emergency Medical Services dispatch, transport, and prehospital notification, we hope that the onset-to-door time will be improved. Nowadays, the window time for thrombolytic therapy has been increased from 3 to 4.5 hours to recruit more patients for the treatment.1 An observational study38 reported that 60% of patients (398 of 664) were treated between 181 and 200 minutes from admission. These patients would have been missed if a 3-hour cutoff had been used. In our study, 18 patients (11%) were out of the 3hour window and excluded because of the primary diagnostic evaluations. Our mean door-to-needle time of 58 minutes, although concordant with other studies,39-42 highlights the need for further education and increased awareness of nurses, residents, and peers. Our stroke unit with just 18 beds is the only tertiary referral center for the city of Mashhad (with a population of more than 2.5 million citizens) and 3 surrounding provinces (with a total population of 6 million). Consequently, we may have missed many eligible patients because they lived a long way from our center. Although there is no standard definition for the supply of stroke units in various cities and countries, the number of stroke units per 100,000 population in 7 European countries showed a variation from .15 to .93, which is tending to increase over time.43 Therefore, the number of stroke centers in Iran should be increased and adjusted to the size and population of each area to minimize the delay in patients’ arrival time.44 The clinical efficacy and safety of lower dosage of rtPA are approved in Japan (.6 mg/kg body weight; maximum 60 mg).13 However, compared with the criteria recommended in the American, European, and Japanese guidelines for rtPA (Alteplase) administration,1,13,45 we used a different selection criteria for the present study, which was based on a general consensus between the members of the stroke center with respect to the socioeconomic infrastructural limitations and previous experience. According to the American, European, and Japanese guidelines, patients of 80 years or younger and an NIHSS score of 25 or less are generally considered eligible for thrombolysis, whereas we did not enroll patients older than 75 years and an NIHSS score more than 20 and those arrived after 3 hours from the onset of stroke. Moreover, expansion of the time window from 3 to 4.5 hours from the onset of the event is nowadays recommended.9,46 Thus, unraveling the available limitations, we need to adjust the clinical application of rtPA in our center to the generally approved criteria, which might favor more stroke patients with improving neurologic outcomes. In the present study, despite using a lower dosage of rtPA (almost equivalent to the Japanese study) instead
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Figure 2. Mean rate of rtPA–treated patients during the treatment periods among all eligible patients with acute ischemic stroke admitted within 3 hours from symptom onset in different studies in developed and developing countries, including the present study. The studies were not homogenous in the data provided. Nevertheless, they used almost similar selection criteria, particularly for the 3-hour window time. Because the frequency of rtPA therapy varied between hospitals in 1 country, the rates are reported as the lowest and highest rates according to the literature. The ratios of rtPA administration within 1 year of follow-up were either directly mentioned in the corresponding study or calculated from the total rates within the time period of the study to find the mean yearly ratios of rtPA administration. Abbreviation: rtPA, recombinant tissue plasminogen activator.
BARRIERS AGAINST THROMBOLYTIC THERAPY IN IRAN Figure 3. Rates of thrombolytic therapy in our study with different selection criteria. (A) Declining trends in rate of rtPA administration applying our exclusion criteria step-by-step (onset to needle time .3 hours, NIHSS score .20, seizure at onset, age .75 years) depicting our fears. (B) The potential trends in case of modifying our inclusion criteria (extending onset-to-needle time to 4.5 hours, NIHSS score to 25, seizure with no evidence of vascular occlusion, age limit to 80 years) illustrates the prospects of rtPA therapy and our hopes. Note: We did not have enough data about the 980 patients who were initially excluded because of the late onset-to-door time of .3 hours, thus not considered in the rate estimate of the potential rtPA therapy with the modified criteria. Abbreviations: NIHSS, National Institutes of Health Stroke Scale; rtPA, recombinant tissue plasminogen activator.
A
of the American Heart Association/American Stroke Association guideline (.9 mg/kg body weight),1,7 we achieved positive result of 50% favorable outcome and 75% decrease in NIHSS scores at 3 months from the treatment without any mortality or SICH compared with the mean SICH rates of 7.5% and mortality rates of 15.7% in the previous 7 major trials with a cumulative population of 2,124 patients.42 Moreover, 3 months after the treatment, favorable outcomes (mRS scoring 0-1) were noted for half of our participants, comparable with the reported range of 51%-63% in the literature.7,47-49 However, the number of patients receiving rtPA is very small, and the changes in the NIHSS and mRS scores cannot be generalized. These findings, along with the positive experience in Japan, may imply a limitation in the efficacy of the higher dose of rtPA than a specific dose in treatment of AIS, which needs to be evaluated. In spite of the low rate of rtPA administration for AIS in our study compared with the developed countries, thrombolytic therapy seems feasible in Iran. With some modifications to the selection criteria, we could have increased the rate of rtPA in our center to at least 6.3% (72 of 1,144; Fig 3). It is clear that more stroke awareness campaigns are needed to improve timely access to thrombolysis and stroke care in Iran. This study assessed the implementation of thrombolytic therapy in the northeast of Iran. Besides, the hurdles and limitations of administration of rtPA for AIS in Iran as a developing country have been explored. Nevertheless, the low number of enrolled patients and the fixed dosage of rtPA, which was lower than that of in the international protocols, were the main limitations of the present study. Although these 2 points were induced by many socioeconomic infrastructural obstacles and also lack of prior experience with rtPA in AIS in our center, assessing the efficacy and safety of the lower dosage of rtPA treatment were not the purpose of this study.
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B
Conclusions Access to thrombolytic therapy in Iran is less than in most developed countries and comparable with other developing ones, which can be partly explained by the poor knowledge of the general population about stroke, insufficient out- and in-hospital resources and stroke facilities. Despite all concerns about rtPA complications, the results of this preliminary study suggest that rtPA is feasible and effective in a developing country like Iran and furthermore raise hopes about the effective treatment of AIS. Public campaigns and teamwork including health care professionals and policy makers with the support of scientific organizations would help to improve stroke care delivery in Iran as a developing country. Acknowledgments: The authors would like to acknowledge the support of Asib-Paziran-Toos Charity Organization and the commitment of Ghaem Hospital Stroke Unit staff and nurses in treating the patients and adhering to the treatment protocol.
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K. NIKKHAH ET AL. 21. Kono S, Deguchi K, Morimoto N, et al. Tissue plasminogen activator thrombolytic therapy for acute ischemic stroke in 4 hospital groups in Japan. J Stroke Cerebrovasc Dis 2013;22:190-196. 22. Sharma VK, Tsivgoulis G, Tan JH, et al. Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore. J Stroke Cerebrovasc Dis 2010;19:424-430. 23. Yoshimura S, Egashira Y, Sakai N, et al. Retrospective nationwide survey of acute stroke due to large vessel occlusion in Japan: a review of 1,963 patients and the impact of endovascular treatment. Cerebrovasc Dis 2011; 32:219-226. 24. Singer OC, Hamann GF, Misselwitz B, et al. Time trends in systemic thrombolysis in a large hospital-based stroke registry. Cerebrovasc Dis 2012;33:316-321. 25. Reeves MJ, Arora S, Broderick JP, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke 2005; 36:1232-1240. 26. de Carvalho JJ, Alves MB, Viana GA, et al. Stroke epidemiology, patterns of management, and outcomes in Fortaleza, Brazil: a hospital-based multicenter prospective study. Stroke 2011;42:3341-3346. 27. Nguyen TH, Truong AL, Ngo MB, et al. Patients with thrombolysed stroke in Vietnam have an excellent outcome: results from the Vietnam thrombolysis registry. Eur J Neurol 2010;17:1188-1192. 28. Nilanont Y, Nidhinandana S, Suwanwela NC, et al. Quality of acute ischemic stroke care in Thailand: a prospective multicenter countrywide cohort study. J Stroke Cerebrovasc Dis 2014;23:213-219. 29. Padma MV, Singh MB, Bhatia R, et al. Hyperacute thrombolysis with IV rtPA of acute ischemic stroke: efficacy and safety profile of 54 patients at a tertiary referral center in a developing country. Neurol India 2007;55:46-49. 30. Sharma SR, Sharma N. Hyperacute thrombolysis with recombinant tissue plasminogen activator of acute ischemic stroke: feasibility and effectivity from an Indian perspective. Ann Indian Acad Neurol 2008; 11:221-224. 31. Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic therapy in acute ischemic stroke in Asia: the first prospective evaluation. Clin Neurol Neurosurg 2006;108:549-552. 32. Wasay M, Barohi H, Malik A, et al. Utilization and outcome of thrombolytic therapy for acute stroke in Pakistan. Neurol Sci 2010;31:223-225. 33. Durai Pandian J, Padma V, Vijaya P, et al. Stroke and thrombolysis in developing countries. Int J Stroke 2007; 2:17-26. 34. Kwan J, Hand P, Sandercock P. A systematic review of barriers to delivery of thrombolysis for acute stroke. Age Ageing 2004;33:116-121. 35. Katzan IL, Sila CA, Furlan AJ. Community use of intravenous tissue plasminogen activator for acute stroke: results of the brain matters stroke management survey. Stroke 2001;32:861-865. 36. Sharma VK, Ng KW, Venketasubramanian N, et al. Current status of intravenous thrombolysis for acute ischemic stroke in Asia. Int J Stroke 2011;6:523-530. 37. Tong D, Reeves MJ, Hernandez AF, et al. Times from symptom onset to hospital arrival in the Get with the Guidelines—Stroke Program 2002 to 2009: temporal trends and implications. Stroke 2012;43:1912-1917. 38. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke
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(SITS-ISTR): an observational study. Lancet 2008; 372:1303-1309. Alberts MJ, Latchaw RE, Selman WR, et al. Recommendations for comprehensive stroke centers: a consensus statement from the brain attack coalition. Stroke 2005; 36:1597-1616. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 2011;123:750-758. Nadeau JO, Shi S, Fang J, et al. tPA use for stroke in the Registry of the Canadian Stroke Network. Can J Neurol Sci 2005;32:433-439. Seet RC, Rabinstein AA. Symptomatic intracranial hemorrhage following intravenous thrombolysis for acute ischemic stroke: a critical review of case definitions. Cerebrovasc Dis 2012;34:106-114. Moon L. Stroke treatment and care: a comparison of approaches in OECD countries. In: A disease-based comparison of health systems: what is best and at what cost? Paris, France: OECD Publishing 2003:53-76. Ahuja C, Mamdani M, Saposnik G, Stroke Outcomes Research Canada Working Group. Influence of socioeco-
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Background: Insufficient information is available on the barriers that explain low rates of thrombolytic therapy for acute ischemic stroke (AIS) in developing countries compared with rates in developed societies. By the present study, we aimed to assess the implementation of thrombolytic therapy in the northeast of Iran to explore the gaps and hurdles against thrombolysis as the generally accepted treatment for AIS. Methods: In a 1-year cohort study among AIS patients admitted to the second largest tertiary neurologic referral center in Iran, those who met the prespecified selection criteria were treated with intravenous recombinant tissue plasminogen activator (rtPA). Results: Among 1,144 patients admitted with AIS, only 14 (1.2%) were treated with rtPA. The mean onset-to-needle and door-to-needle times were 172 and 58 minutes, respectively; 980 (85.6%) patients were initially excluded from the study because of late arrival. Additionally, 60 patients in total were omitted because of either their high age (3.7%) or passing the gold standard time limit for rtPA therapy after preliminary evaluations (1.6%), and 90 more patients (7.9%) were considered not suitable for thrombolysis because of the severity of the symptoms or the higher risk of bleeding on rtPA. Conclusions: Access to thrombolytic therapy for AIS in Iran is less than in most developed countries but comparable with other developing countries. Awareness campaigns are needed to minimize barriers and improve access to thrombolysis and specialized stroke care in Iran. Key Words: Stroke— thrombolysis—developing countries—stroke facilities—cohort study—treatment. Ó 2015 by National Stroke Association
From the *Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; †Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; ‡Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; xClinical Epidemiology Program, Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; kToronto Health Economics and Technology Assessment Collaborative, University of Toronto, Toronto, Ontario, Canada; {Department of Neurology, Goethe-University, Frankfurt am Main, Germany; #The Division of Neurology, Department of Medicine, Stroke Outcomes Research Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; **Department of Community and Preventive Medicine, School of Medicine, Mashhad University of Medical
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Sciences, Mashhad, Iran; ††Department of Radiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; and ‡‡Comprehensive Stroke Center, Department of Neurology, University of Alabama, Birmingham, Alabama. Received July 10, 2014; revision received September 4, 2014; accepted September 7, 2014. Address correspondence to Mahmoud Reza Azarpazhooh, MD, Department of Neurology, Ghaem Hospital, Taghi Abad Square, Mashhad, 91766-99199, Iran. E-mail: [email protected]. 1 These authors contributed equally to this work. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.012
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 2 (February), 2015: pp 408-415
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Introduction Stroke is the leading cause of functional impairment1 and the second most common cause of mortality in developed and developing countries.2 Many survivors had debilitating disabilities and low quality of life, along with high financial burdens of lifelong care and rehabilitation.3 An estimated 2%-5% of the total health care expenditures in western countries are dedicated to the diagnosis and treatment of stroke.4,5 Because of geographic variations, controversial results, and a lack of well-designed community-based studies, the incidence rates and outcome of stroke are not well characterized in Middle East countries. Our recent large population-based study showed that in Iran, compared with developed countries, the incidence of stroke was higher and its occurrence was about 1 decade earlier.6 Considering these findings, the burden of stroke in Iran appears to be enormous and has to be considered as a public health priority. Although primary prevention is definitely the best way to control the rate of stroke, this devastating situation can also be combated by assessing the suitability of thrombolytic therapy as the available effective treatment for acute ischemic stroke (AIS). Early administration of intravenous recombinant tissue plasminogen activator (rtPA) proved to be effective in reducing mortality, improving neurologic outcomes, and limiting lesion growth.7,8 The earlier the treatment is administered, the more effective it might be and the better the prognosis for the patients.9 rtPA has been found to be a cost-effective treatment for AIS in developed countries.10 Despite the high rate of stroke in Iran, rtPA for AIS has rarely been used in daily practice.6 The possible consequences and cost of rtPA therapy, along with its sparse medication distribution and insufficient prehospital and posthospital infrastructures, deter against its widespread use and sometimes make it ‘‘fearsome.’’ In this study, we aimed to assess the feasibility, but not the efficacy or outcome, of rtPA therapy to find and overcome barriers against its routine administration among patients with AIS in Mashhad, the second largest city in Iran.
Methods Design The investigation is a cohort study, approved by the Research Ethics Board, Mashhad University of Medical Sciences (no. 89728). Written informed consent was provided by patients or their next of kin before enrolling into the study.
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more than 2.5 million citizens, is the second most populated city of Iran. During a 1-year study period (from September 2011 to September 2012), all patients with AIS who met our inclusion criteria for rtPA therapy, which were mainly according to the 2010 American Heart Association/American Stroke Association stroke guideline11 and the Alberta Stroke Program Early Computed Tomography Score,12 were enrolled in the study (Fig 1). However, some criteria were modified according to the barriers and access to rtPA, particularly regarding the cost. Patients older than 75 years and those who passed the 3-hour window time for thrombolytic therapy after evaluation were excluded from the study mainly because of physicians’ concerns for rtPA complications. Demographic characteristics and medical and laboratory histories were recorded for each individual patient. Furthermore, we recorded the mean time from symptom onset to admission (onset to door), admission to computed tomography (CT) (door to CT scan), admission to treatment (door to needle), and symptom onset to rtPA treatment (onset to needle).
Treatment Protocol Eligible patients were treated with one 50-mg vial of rtPA; 10% of the vial (ie, 5 mg) was slowly infused within 1 minute, and the remaining was infused within the following 60 minutes. Considering the lack of 10-mg vials, in particular, and the relatively high out-of-pocket cost in Iran, we used a lower dosage of rtPA, comparable with the effective .6 mg/kg dose as reported from Japan.13
Outcomes The primary outcomes were the rate of rtPA administration during the study period. The National Institutes of Health Stroke Scale (NIHSS) was used to quantify the level of impairment caused by stroke, and the modified Rankin Scale (mRS) was used to quantify the degree of patients’ improvements in doing their daily activities.7 We considered an mRS score of 0-1 at 3 months after treatment and also improvement by more than 4 in NIHSS at 2 hours and 3 months after rtPA as favorable outcomes. We also measured safety outcome, defined as mortality, brain edema, cardiac arrhythmia, orolingual angioedema, and asymptomatic intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage (SICH) because of thrombolytic therapy. Based on the Canadian Stroke Network definition,14 SICH was defined as any ICH resulting in neurologic deficit during the first 36 hours of rtPA treatment. Furthermore, the length of hospital stay was also recorded for each patient.
Population The study was performed at the stroke unit of Ghaem Hospital, a tertiary neurologic referral center in Mashhad in the northeast of Iran. Mashhad, with a population of
Data Analysis SPSS 11.5 (SPSS Inc., Chicago, IL) was used for all statistical analyses. Standard descriptive statistics were
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Figure 1. Target population for rtPA treatment in acute ischemic stroke patients based on the inclusion and exclusion criteria. ‘‘*,’’ 22 of 164 cases had more than 1 exclusion criterion, including 12 cases overlapped with the age limit, 4 also passed 3-hour window time after evaluations, and 6 in 13 other criteria. Abbreviations: ASPECT, Alberta Stroke Program Early CT Score; CT, computed tomography; CVA, cerebrovascular ischemic attack; DBS, diastolic blood pressure; GIB, gastrointestinal bleeding; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.
applied to describe the pattern of the data. A chi-square test was used to examine the significance of the association between categorical data. The data were checked with a Kolmogorov–Smirnov test for normal distribution. For continuous data, t test and Mann–Whitney U test were used as indicated. A 2-tailed P value of less than .05 was considered to be significant.
Results During the study period, 1,144 patients with AIS were admitted, of whom a small proportion (n 5 164 patients, 14.3%) was admitted within the first 3 hours of symptom onset (Fig 1). A total of 22 patients of 164 had more than 1 exclusion criterion. Finally, 14 patients (1.2%; 9 men and 5 women) received rtPA therapy.
The mean baseline NIHSS score of the 14 treated patients was 14.1 6 2.7 (range 9-18) before rtPA therapy. After the treatment, this value was reduced to 5.8 6 4.3 (range 0-18) after 2 hours (ie, a 59% reduction) and to 3.4 6 2.9 (range 0-18) after 3 months (ie, a 75.7% reduction; P , .001). The NIHSS scores were significantly improved by more than 75% in more than half of the patients (8 of 14) and by more than 50% in 85.7% of the patients (12 of 14). Three patients reached the NIHSS score of 0 at 3 months after the treatment. Half of the participants (7 of 14) reported favorable outcomes (mRS scoring 0-1) 3 months after the treatment, whereas 2 patients had an mRS score of 2 and the other 5 patients had an mRS score of 3 or more. All 14 patients survived at 3 months after the treatment. The mean age of these 14 patients was 54.9 6 11.3 years (range 35-75), with no significant difference between
BARRIERS AGAINST THROMBOLYTIC THERAPY IN IRAN
genders (P 5 .53). The mean onset-to-door time and to be visited by the on-call neurologist were 113.2 6 21.3 (range 60-135) and 19.3 6 4.3 (range 15-30) minutes, respectively. The mean door-to-CT scan time was 14.3 6 5.1 minutes (range 10-25). The mean onset-to-needle and door-toneedle times were 172.1 6 13.1 (range 135-180) and 57.6 6 8.2 (range 48-66) minutes, respectively. The 2 most common complications of rtPA treatment were brain edema (4 of 14) and bradycardia (4 of 14). Asymptomatic ICH happened in 2 patients; 1 was accompanied by intraventricular hemorrhage. We did not observe SICH nor any orolingual angioedema or other hemorrhagic events (including gastrointestinal and urologic bleeding and dermal purpura or ecchymosis) during the study period.
Discussion Early administration of rtPA has been shown to significantly improve clinical outcomes and decrease mortality after AIS.7,15 Although the majority of the stroke burden worldwide occurs in developing countries with a 10year earlier stroke onset,6,16 a ‘‘fearful’’ attitude exists in such countries regarding the potential complications of rtPA. In the present study, only 14 (1.2%) patients with AIS were treated with rtPA during the 1-year study period. A recent systematic review17 assessed the global use of rtPA for AIS among 214 countries and found that only 54 (25%) of these countries reported its administration, ranging from as low as 3% (1 of 36) of low-income, to 13% (7 of 54) of lower middle-income, to 28% (15 of 54) of upper middle-income, and to 44% (31 of 70) of highincome countries.17 In comparison, access to rtPA in Iran is lower than in most of the developed countries1825 but comparable with other developing countries26-32 (Fig 2). The barriers of timely administration of rtPA in developing countries include limited resources, prehospital delay, sparse numbers of stroke units,16,33 poor stroke awareness in the general population,33 lack of general knowledge and professional education,33,34 the high cost of rtPA, lack of insurance coverage, low socioeconomic status of patients,16,33 and physician reluctance and concerns about the benefits compared with its serious side effects, especially bleeding.34-36 Time from symptom onset to hospital arrival is the most important factor in choosing the right patients for thrombolytic therapy.37 In our study, 85.7% of our admitted patients were excluded because of late arrival to the hospital (after 3 hours; Fig 3). In Canada and the United States, about 75% of AIS patients presented to hospital after 3 hours of symptom onset.35,37 Hospital arrival in busy urban settings in developing countries can be significantly delayed because of road traffic. To address this problem in our setting, in collaboration with Mashhad Traffic and Transportation Organization, we
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designed an online Emergency Medical Services Traffic System to control the traffic lights and direct the ambulance driver to the quickest least congested pathway route to the hospital. With better education and improved infrastructural facilities, such as rapid Emergency Medical Services dispatch, transport, and prehospital notification, we hope that the onset-to-door time will be improved. Nowadays, the window time for thrombolytic therapy has been increased from 3 to 4.5 hours to recruit more patients for the treatment.1 An observational study38 reported that 60% of patients (398 of 664) were treated between 181 and 200 minutes from admission. These patients would have been missed if a 3-hour cutoff had been used. In our study, 18 patients (11%) were out of the 3hour window and excluded because of the primary diagnostic evaluations. Our mean door-to-needle time of 58 minutes, although concordant with other studies,39-42 highlights the need for further education and increased awareness of nurses, residents, and peers. Our stroke unit with just 18 beds is the only tertiary referral center for the city of Mashhad (with a population of more than 2.5 million citizens) and 3 surrounding provinces (with a total population of 6 million). Consequently, we may have missed many eligible patients because they lived a long way from our center. Although there is no standard definition for the supply of stroke units in various cities and countries, the number of stroke units per 100,000 population in 7 European countries showed a variation from .15 to .93, which is tending to increase over time.43 Therefore, the number of stroke centers in Iran should be increased and adjusted to the size and population of each area to minimize the delay in patients’ arrival time.44 The clinical efficacy and safety of lower dosage of rtPA are approved in Japan (.6 mg/kg body weight; maximum 60 mg).13 However, compared with the criteria recommended in the American, European, and Japanese guidelines for rtPA (Alteplase) administration,1,13,45 we used a different selection criteria for the present study, which was based on a general consensus between the members of the stroke center with respect to the socioeconomic infrastructural limitations and previous experience. According to the American, European, and Japanese guidelines, patients of 80 years or younger and an NIHSS score of 25 or less are generally considered eligible for thrombolysis, whereas we did not enroll patients older than 75 years and an NIHSS score more than 20 and those arrived after 3 hours from the onset of stroke. Moreover, expansion of the time window from 3 to 4.5 hours from the onset of the event is nowadays recommended.9,46 Thus, unraveling the available limitations, we need to adjust the clinical application of rtPA in our center to the generally approved criteria, which might favor more stroke patients with improving neurologic outcomes. In the present study, despite using a lower dosage of rtPA (almost equivalent to the Japanese study) instead
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Figure 2. Mean rate of rtPA–treated patients during the treatment periods among all eligible patients with acute ischemic stroke admitted within 3 hours from symptom onset in different studies in developed and developing countries, including the present study. The studies were not homogenous in the data provided. Nevertheless, they used almost similar selection criteria, particularly for the 3-hour window time. Because the frequency of rtPA therapy varied between hospitals in 1 country, the rates are reported as the lowest and highest rates according to the literature. The ratios of rtPA administration within 1 year of follow-up were either directly mentioned in the corresponding study or calculated from the total rates within the time period of the study to find the mean yearly ratios of rtPA administration. Abbreviation: rtPA, recombinant tissue plasminogen activator.
BARRIERS AGAINST THROMBOLYTIC THERAPY IN IRAN Figure 3. Rates of thrombolytic therapy in our study with different selection criteria. (A) Declining trends in rate of rtPA administration applying our exclusion criteria step-by-step (onset to needle time .3 hours, NIHSS score .20, seizure at onset, age .75 years) depicting our fears. (B) The potential trends in case of modifying our inclusion criteria (extending onset-to-needle time to 4.5 hours, NIHSS score to 25, seizure with no evidence of vascular occlusion, age limit to 80 years) illustrates the prospects of rtPA therapy and our hopes. Note: We did not have enough data about the 980 patients who were initially excluded because of the late onset-to-door time of .3 hours, thus not considered in the rate estimate of the potential rtPA therapy with the modified criteria. Abbreviations: NIHSS, National Institutes of Health Stroke Scale; rtPA, recombinant tissue plasminogen activator.
A
of the American Heart Association/American Stroke Association guideline (.9 mg/kg body weight),1,7 we achieved positive result of 50% favorable outcome and 75% decrease in NIHSS scores at 3 months from the treatment without any mortality or SICH compared with the mean SICH rates of 7.5% and mortality rates of 15.7% in the previous 7 major trials with a cumulative population of 2,124 patients.42 Moreover, 3 months after the treatment, favorable outcomes (mRS scoring 0-1) were noted for half of our participants, comparable with the reported range of 51%-63% in the literature.7,47-49 However, the number of patients receiving rtPA is very small, and the changes in the NIHSS and mRS scores cannot be generalized. These findings, along with the positive experience in Japan, may imply a limitation in the efficacy of the higher dose of rtPA than a specific dose in treatment of AIS, which needs to be evaluated. In spite of the low rate of rtPA administration for AIS in our study compared with the developed countries, thrombolytic therapy seems feasible in Iran. With some modifications to the selection criteria, we could have increased the rate of rtPA in our center to at least 6.3% (72 of 1,144; Fig 3). It is clear that more stroke awareness campaigns are needed to improve timely access to thrombolysis and stroke care in Iran. This study assessed the implementation of thrombolytic therapy in the northeast of Iran. Besides, the hurdles and limitations of administration of rtPA for AIS in Iran as a developing country have been explored. Nevertheless, the low number of enrolled patients and the fixed dosage of rtPA, which was lower than that of in the international protocols, were the main limitations of the present study. Although these 2 points were induced by many socioeconomic infrastructural obstacles and also lack of prior experience with rtPA in AIS in our center, assessing the efficacy and safety of the lower dosage of rtPA treatment were not the purpose of this study.
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B
Conclusions Access to thrombolytic therapy in Iran is less than in most developed countries and comparable with other developing ones, which can be partly explained by the poor knowledge of the general population about stroke, insufficient out- and in-hospital resources and stroke facilities. Despite all concerns about rtPA complications, the results of this preliminary study suggest that rtPA is feasible and effective in a developing country like Iran and furthermore raise hopes about the effective treatment of AIS. Public campaigns and teamwork including health care professionals and policy makers with the support of scientific organizations would help to improve stroke care delivery in Iran as a developing country. Acknowledgments: The authors would like to acknowledge the support of Asib-Paziran-Toos Charity Organization and the commitment of Ghaem Hospital Stroke Unit staff and nurses in treating the patients and adhering to the treatment protocol.
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