Worldwide reported use of IV tissue plasminogen activator for acute ischemic stroke

Worldwide reported use of IV tissue plasminogen activator for acuteischemic stroke

Aaron L. Berkowitz1, Manoj K. Mittal2, Hannah C. McLane3, Gordon C. Shen4,RajaNandini Muralidharan5, Jennifer L. Lyons1, Russell T. Shinohara6, Ashfaq Shuaib7, andFarrah J. Mateen8,9*

Background and Purpose Intravenous tissue plasminogen acti-vator is the most effective treatment for acute ischemic stroke,and its use may therefore serve as an indicator of the availablelevel of acute stroke care. The greatest burden of stroke is inlow- and middle-income countries, but the extent to whichintravenous tissue plasminogen activator is used in thesecountries is unreported.Summary of Review A systematic review was performedsearching each country name AND ‘stroke’ OR ‘tissue plasmino-gen activator’ OR ‘thrombolysis’ using PubMed, Embase, GlobalHealth, African Index Medicus, and abstracts published in theInternational Journal of Stroke (Jan. 1, 1996–Oct. 1, 2012). Thereported use of intravenous tissue plasminogen activator wasthen analyzed according to country-level income status, totalexpenditure on health per capita, and mortality and disability-adjusted life years due to stroke. There were 118 780 citationsreviewed. Of 214 countries and independent territories, 64(30%) reported use of intravenous tissue plasminogen activatorfor acute ischemic stroke in the medical literature: 3% (1/36)low-income, 19% (10/54) lower-middle-income, 33% (18/54)upper-middle-income, and 50% (35/70) high-income-countries(test for trend, P < 0·001). When considering country-leveldeterminants of reported intravenous tissue plasminogen acti-vator use for acute ischemic stroke, total healthcare expendi-ture per capita (odds ratio 3·3 per 1000 international dollarincrease, 95% confidence interval 1·4–9·9, P = 0·02) andreported mortality rate from cerebrovascular disease (oddsratio 1·02, 95% confidence interval 0·99–1·06, P = 0·02) weresignificant, but reported disability-adjusted life years from

cerebrovascular diseases and gross national income per capitawere not (P > 0·05). Of the 10 countries with the highestdisability-adjusted life years due to stroke, only one reportedintravenous tissue plasminogen activator use.Conclusions By reported use, intravenous tissue plasminogenactivator for acute ischemic stroke is available to somepatients in approximately one-third of countries. Access toadvanced acute stroke care is most limited where the greatestburden of cerebrovascular disease is reported.Key words: epidemiology, global health, stroke, thrombolysis

Introduction

In 2010, there were 2·8 million deaths and 39·4 million disability-

adjusted life years (DALYs) lost because of acute ischemic stroke

(AIS) (1,2). Several calls have been made to combat the epidemic

of stroke globally, including coordinated efforts for stroke preven-

tion, intervention, and rehabilitation (3). With respect to acute

therapy, intravenous tissue plasminogen activator (IV-tPA) is the

most effective emergent treatment for AIS (4); however, nearly

90% of all strokes are estimated to occur in low- and middle-

income countries (LMIC) (5) where the least data are available on

IV-tPA use (6). It remains unknown to what extent IV-tPA is used

globally, particularly in LMIC, where the necessary resources and

personnel to provide acute care for AIS may be limited (6).

Barriers to the use of IV-tPA have been reported at the indi-

vidual and hospital levels in several studies from high-income

(7,8) and, to a much lesser extent, lower income settings (6,9).

These studies emphasize both prehospital and within-hospital

factors, such as limited awareness of stroke symptoms and signs

among both patients and physicians, limited access to or delay in

obtaining neuroimaging, and physician reluctance to provide

IV-tPA in complex clinical scenarios. Most clinical studies have

concentrated on patient- and physician-level factors (7–9), as well

as local geographic factors (10) that preclude the use of IV-tPA for

AIS within a narrow therapeutic time window.

However, treatment of AIS with IV-tPA also depends on factors

that extend beyond the individual patient, healthcare worker, and

hospital. Here we systematically review the published medical

literature on the use of IV-tPA for AIS in all countries and report

these data in relation to recognized and internationally employed

country-level indicators.

Methods

We searched for reported IV-tPA use for treatment of AIS using

individual countries and independent territories as the unit of

analysis. All data on IV-tPA use were derived from the published

Correspondence: Farrah J. Mateen*, Department of Neurology, AC-720,Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.E-mail: [email protected] of Neurology, Brigham and Women’s Hospital, HarvardMedical School, Boston, MA, USA2Department of Neurology, The University of Kansas Medical Center,Kansas City, KS, USA3School of Public Health, Harvard University, Boston, MA, USA4Health Policy and Management Division, School of Public Health,University of California, Berkeley, CA, USA5Division of Neurocritical Care, Department of Neurology, Universityof Pennsylvania, Philadelphia, PA, USA6Department of Biostatistics and Epidemiology, Perelman School ofMedicine, University of Pennsylvania, Philadelphia, PA, USA7Division of Neurology, Department of Internal Medicine, University ofAlberta, Edmonton, AB, Canada8Department of Neurology, Massachusetts General Hospital, Boston, MA,USA9Department of International Health, Bloomberg School of Public Health,The Johns Hopkins University, Baltimore, MD, USA

Received: 12 June 2013; Accepted: 30 August 2013; Published online10 November 2013

Conflicts of interest: None declared.

Funding: None

DOI: 10.1111/ijs.12205

Systematic review

© 2013 The Authors.International Journal of Stroke © 2013 World Stroke Organization

Vol 9, April 2014, 349–355 349

literature indexed in medical databases and reported via medical

publications. Data on country level indicators were taken from

recognized international agencies including the World Bank (11),

World Health Organization (12), and Global Burden of Disease

Program (13).

Search strategyWe performed a systematic review of all literature related to the

use of IV-tPA for AIS found in PubMed (Medline), Embase,

Global Health, African Index Medicus, and abstracts from stroke

conferences found in the International Journal of Stroke. Standard

methods for systematic reviews of observational and interven-

tional studies were employed (14). Our search strategy, study

questions, and statistical analyses were all specified prior to

data collection. The dates of inclusion for retrieved articles were

January 1, 1996 to August 31, 2012, the date of censoring for our

literature search. In the case of the International Journal of Stroke,

the year of search began in 2006, the first year of publication of

abstracts in the journal. The end date of the Embase search was

December 31, 2012. Search terms included ‘stroke’, ‘thrombolysis’,

and ‘tissue plasminogen activator’. These same terms [MeSH]

were searched for each country using its political name and

various geographic region names (e.g. ‘Middle East’ or ‘Africa’)

(Supplemental Methods). In the case of countries with more than

one name or multiple words in the name, multiple searches were

performed for a country. For example, ‘Iran’ and ‘Islamic Republic

of Iran’ were both searched, ‘Burma’ and ‘Myanmar’ were both

searched, and ‘Turks’ and ‘Caicos’ were searched separately. The

country list was derived from the World Health Organization and

World Bank lists of member countries and independent territo-

ries (2012) (11). Articles in any language were included.

Results for each country were assessed by two independent

physician reviewers. Reviews included full text articles. Each

reviewer completed a standardized form in Microsoft Excel®

to address the following questions: (a) ‘Is there any report of

IV-tPA use for AIS in the country?’ and (b) ‘If there is a report of

IV-tPA use, what is the highest quality of clinical study reported:

hypothesis-driven study, case series, or case report?’ Included

studies had to be original reports of IV-tPA for AIS in humans

with a clear indication that IV-tPA was used in the country, either

through the correspondence address listed in the country of inter-

est or by the authors’ indication that the study was performed in

that country. Review articles and commentaries were also read

and their reference lists reviewed for other possible sources of

information about IV-tPA use.

Inter-reviewer disagreements were resolved by employing

a third reviewer to repeat the search strategy. A third review

was performed if there was discordance on either primary study

question.

Other sources of country-level dataCountry income level was determined by the World Bank atlas

method for categorization based on 2011 gross national income

per capita as low (≤1025 USD), lower middle (1026–4035 USD),

upper middle (4036–12475 USD), and high (≥12 476 USD) (11).

Geographical region was determined by the World Health Orga-

nization classification into one of six regions: African, Americas,

Eastern Mediterranean, European, Southeast Asian, and Western

Pacific (12). The age-adjusted number of DALYs and total mortal-

ity because of cerebrovascular disease were taken from the Global

Burden of Disease analysis (2004) (13). Total healthcare expendi-

ture per capita (2010) and gross national income per capita in

international dollars were taken from the World Health Organiza-

tion and World Bank websites (11). A small number of countries

reported gross national income per capita in 2011 but not in 2010;

therefore, the 2011 gross national incomes per capita were reported

for these countries (The Bahamas, Barbados, Kuwait, and Qatar).

Data analysisThe primary outcome of interest was reported use of IV-tPA for

AIS (yes vs. no), stratified by various country level indicators.

Wilcoxon rank-sum tests were used to compare the expenditure

within each income level between countries reporting IV-tPA use

for AIS and those not reporting IV-tPA use for AIS. Logistic

regression was used to calculate the odds of reported IV-tPA

use and 95% confidence intervals given country-level factors

including gross national income per capita, world region, DALYs

from stroke, and mortality from stroke. Logistic regression was

also used to compare the odds of reported IV-tPA use between

predefined country income groups (low, lower-middle, upper-

middle, and high). All statistical calculations were conducted

using the R statistical package (version 2·14·2, R Foundation for

Statistical Computing, Vienna, Austria, 2012).

Results

Database search resultsWe retrieved 113 988 citations in PubMed, 1071 in Embase, 354 in

Global Health, 23 in African Index Medicus, and 3344 related

conference abstracts in the study timeframe (total 118 780 cita-

tions). All citations in Global Health and abstracts were published

in English. In PubMed, 106 227 citations were in English (93·2%).

Citations were first reviewed by title and abstract, almost all of

which were translated into English. Citations in which IV-tPA use

or study quality could not be discerned from the abstract were

reviewed in full text form. Citations that were not in English

but had a relevant title and abstract to the study question were

also retrieved in full text form. At least one of the review team

members was fluent in Spanish, French, Mandarin, and Hindi.

Reported use of IV-tPAOf 214 countries and independent territories, 64 (30%) reported

use of IV-tPA for AIS, including 3% of low-income countries

(1 of 36), 19% of lower-middle-income-countries (10 of 54), 33%

of upper-middle-income (18 of 54), and 50% of high-income

countries (35 of 70) (test for trend P < 0·001) (Table 1, Fig. 1).

Distribution of countries reporting IV-tPA use for AIS is shown

by country level income status in Fig. 2.

Study quality related to reported IV-tPA useAmong countries reporting IV-tPA use, the best study quality

was original, hypothesis-driven research in 44 (69%), case series

in 17 (27%), and case report in three (5%). The single low-income

country that reported IV-tPA use did so by case report. Among

the 10 lower-middle-income countries that reported IV-tPA use,

Systematic review A. L. Berkowitz et al.


350 Vol 9, April 2014, 349–355

Table 1 Countries with reported use of IV-tPA by gross national income per capita World Bank Group

High-income(out of 70 possible countries)

Upper-middle income(out of 54 possible countries)

Lower-middle income(out of 54 possible countries)

Low-income(out of 36 possible countries)

AustraliaAustriaBelgiumCanadaCroatiaCzech RepublicDenmarkEstoniaFinlandFranceGermanyGreeceHong KongHungaryIrelandIsraelItalyJapanLuxembourgThe NetherlandsNew ZealandNorwayPolandPortugalQatarSaudi ArabiaSingaporeSlovak RepublicSloveniaSouth KoreaSpainSwedenSwitzerlandUnited KingdomUnited States

ArgentinaBosnia and HerzegovinaBrazilChileChinaColombiaCosta RicaIslamic Republic of IranLatviaLithuaniaMalaysiaMexicoRomaniaRussian FederationSerbiaSouth AfricaThailandTurkey

IndiaIndonesiaMoldovaPakistanPhilippinesSenegalSri LankaUkraineUzbekistanVietnam

Kenya

Fig. 1 Map of countries with reported use of IV-tPA.

Systematic reviewA. L. Berkowitz et al.


Vol 9, April 2014, 349–355 351

one did so by case report (10%), four by case series (40%), and

five by hypothesis-driven study (50%). Among the 18 upper-

middle-income countries that reported IV-tPA use, best study

quality was case report in one (6%), case series in nine (50%),

and hypothesis-driven study in eight (44%). Among the 35 high-

income countries with reported IV-tPA use, best study quality in

four countries (11%) was case series, and the remaining 31 coun-

tries (89%) published hypothesis-driven studies (Figs 1 and 2).

Relationship between reported IV-tPA use andhealthcare expenditure per capitaThe median total healthcare expenditure per capita was higher

among countries reporting use of IV-tPA for AIS vs. those not

reporting use (1469 vs. 246 international dollars, P < 0·0001)

and was also higher when considering IV-tPA reporters vs.

nonreporters within the higher country income levels (high-

income countries: 3115·5 vs. 1534·5, P < 0·0001, upper-middle-

income countries: 985 vs. 591·5, P = 0·003). This was not

found in lower income strata (lower-middle-income coun-

tries: 145 vs. 228, P = 0·28, low-income countries: 78 vs. 65,

P = 0·66). None of the countries with the lowest health

expenditure per capita reported use of IV-tPA for AIS, whereas

nine of the 10 countries with the highest health expenditure per

capita reported its use (Table 2). The 10 highest income coun-

tries where IV-tPA use has not been reported are listed in

Table 3.

0.00

0.25

0.50

0.75

1.00

Low Lower Middle Upper Middle High

Income Group

Pro

port

ion

Study TypeCase

Case Series

Hypothesis-Driven

None

Fig. 2 Histogram of countries by reported use of IV-tPA and World Bank Income Group.

Table 2 National total health expenditure per capita and reported IV-tPA use

Top 10 countries by total percapita health expenditure

Total health expenditure percapita (international dollars)

IV-tPAuse

Lowest 10 countries by totalper capita health expenditure

Total health expenditure percapita (international dollars)

IV-tPAuse

United States 8362 Yes Liberia 49 NoLuxembourg 6743 Yes Mozambique 49 NoMonaco 5949 No Burundi 47 NoNorway 5426 Yes Afghanistan 44 NoSwitzerland 5394 Yes Madagascar 41 NoThe Netherlands 5038 Yes Niger 37 NoDenmark 4537 Yes Myanmar 34 NoCanada 4404 Yes Central African Republic 31 NoAustria 4388 Yes Democratic Republic of Congo 27 NoGermany 4332 Yes Eritrea 16 No



352 Vol 9, April 2014, 349–355

Model of country-level indicators for reported IV-tPAuse for AISWhen considering country-level determinants of reported IV-tPA

use for AIS, total healthcare expenditure per capita was significant

[odds ratio 3·3 per 1000 international dollar increase, 95% (CI)

1·4–9·9, P = 0·02] as was mortality rate because of cerebrovascular

disease (odds ratio 1·02, 95% CI 0·99–1·06, P = 0·02), but stroke-

related DALYs and gross national income per capita were not

(P > 0·05) (Table 4). Of the 10 countries with the greatest burden

of stroke-related DALYs, only one country reported IV-tPA use

(Table 5).

Discussion

Although stroke prevention in LMIC is under active study (5,15),

little is reported on acute stroke management in resource-limited

settings. The availability of IV-tPA in higher income countries in

the past 15 years has led to increased community-level efforts

to improve awareness of stroke symptoms, promote emergent

stroke treatment, and reduce stroke disability and death (16,17).

Although associated with a small but significant risk of hemor-

rhage, IV-tPA is considered safe and effective for the majority of

patients with AIS who meet treatment criteria. Poststroke care,

including the establishment of the ‘stroke unit’ in recent decades,

has complemented IV-tPA use to improve stroke outcomes in

many countries (18). In higher income settings, tele-stroke pro-

grams have increased the accessibility of IV-tPA and expert stroke

care even in locations without neurological specialists (19). The

use of IV-tPA requires several successful steps including commu-

nity education and awareness; hospital accessibility; rapid trans-

portation, triage, and neuroimaging; and supportive post-tPA

care. IV-tPA can therefore be considered a measurable indicator of

accessibility to the most advanced emergent stroke treatment.

Our study provides an initial estimate of the number of coun-

tries and independent territories reporting use of IV-tPA for AIS

through indexed medical publications and medical research. Only

30% of all countries and independent territories report IV-tPA

use in the medical literature. Reported use of IV-tPA is strongly

associated with total health care expenditure per capita in a

country, independent of stroke burden, world region, and a coun-

try’s gross national income per capita. Of the 10 countries with

the highest healthcare expenditure per capita, only one country

did not report IV-tPA use (Monaco). In contrast, none of the 10

countries with the lowest healthcare expenditure per capita report

IV-tPA use for AIS. IV-tPA use is more likely in countries with a

higher mortality from cerebrovascular disease, but the effect seen

here was marginal and may represent countries that have under-

gone the last stages of the epidemiologic transition. In contrast,

only one of the 10 countries with the highest stroke-related

DALYs reports IV-tPA use for AIS (Russian Federation). Access to

the highest level of stroke care is likely most limited where the

burden of cerebrovascular disease is greatest. Although IV-tPA

alone does not represent a solution to this problem, it may serve

as an indicator of the worldwide distribution of resources avail-

able for acute stroke care.

Even in LMIC where IV-tPA is available for AIS treatment,

availability, accessibility, and affordability of IV-tPA are limited.

For example, one study in Iran in 2009 found that only seven of

625 AIS patients (1·1%) seen in a seven-month period were eli-

gible for intravenous thrombolysis (20). Major barriers to IV-tPA

were delayed triage and evaluation of hyperacute stroke patients

and drug cost. Only 30% of Iranian patients with a presentation

of AIS could afford IV-tPA. In two separate studies in India

(21,22), IV-tPA use was similarly low for patients medically eli-

gible to receive IV-tPA: five of 22 patients and zero of seven

patients received IV-tPA with the other patients excluded due to

the inability to pay for the drug. IV-tPA costs 1562 USD out of a

Table 3 Top 10 countries by gross national income per capita 2010without reported IV-tPA use for acute ischemic stroke

Countries without reported IV-tPAuse for acute ischemic stroke

Gross national income per capita2010 (international dollars)

Kuwait 53 820Brunei Darussalam 48 760Bahrain 33 530Cyprus 30 160The Bahamas 29 850Iceland 28 630Oman 24 410Trinidad and Tobago 24 000Equatorial Guinea 23 810Malta 23 070

Table 4 Determinants of reported IV-tPA use for acute ischemicstroke*

Country-level determinantOdds ratio(95% CI) P-value

Total Healthcare expenditure per capita(per 1000 international dollars)

3·3 (1·4, 9·9) 0·02

Reported mortality rate fromcerebrovascular disease

1·02 (0·99, 1·06) 0·02

Reported DALYs from cerebrovasculardisease (per 1000 DALYs)

0·03 (0·00, 1·50) 0·09

Gross national income per capita(per 1000 international dollars)

1·00 (0·94, 1·05) 0·86

*Adjusted for WHO World Region.

Table 5 The 10 countries with the most DALYs for stroke and reportedIV-tPA use

Name of the country DALYs for stroke tPA use

Kyrgyz Republic 2078 NoMongolia 1936 NoTuvalu 1876 NoAngola 1867 NoKazakhstan 1818 NoMarshall Islands 1816 NoRussian Federation 1776 YesSt. Kitts and Nevis 1737 NoSierra Leone 1699 NoKiribati 1673 No

DALYs, disability-adjusted life years.



Vol 9, April 2014, 349–355 353

total of 2083 USD for acute stroke care in a single case reported

from a private tertiary referral center in India (23). In Pakistan,

IV-tPA is used in less than 2% of stroke patients and costs nearly

twice the per capita annual income (1200 vs. 672 USD) (24).

Protocol violations were found in 33% of cases in which IV-tPA

was administered with an associated 19% mortality (24). In

Vietnam, a lowered dose of IV-tPA is offered to patients who

cannot afford the full dose of the drug (25). Even without the

administration of IV-tPA, the average stroke patient in Lomé,

Togo, must spend 170 times the annual healthcare expenditure for

acute inpatient stroke care (26).

Given that IV-tPA use is contingent upon rapid identification of

stroke symptoms, immediate transportation of patients to special-

ized healthcare facilities, and rapid access to neuroimaging, it is

perhaps not surprising that many countries do not report its use.

Many countries have no neurologists, decreasing the likelihood of

expert stroke care and published stroke research (27). In 2001, a

survey of African countries revealed that 18 countries had no

computed tomography scanner, 13 countries had just one scanner

each, and 13 countries have more than two scanners each (28).

Many LMIC report significant prehospital admission barriers to

acute stroke treatment such as major traffic jams in some locations

and complete lack of roads or functioning ambulance systems in

others (6,29). Awareness of stroke in some locations is extremely

limited, even among healthcare workers (30). In rural Bangladesh,

for example, more than 90% of stroke deaths occur at home (31).

Relatively little attention has been paid to the population-based

and national indicators that relate to stroke treatment. Govern-

ments may not register or endorse the use of IV-tPA, and knowl-

edge of which hospitals provide thrombolysis in a country may be

limited. National registries, websites, and advertisements listing

hospitals that provide IV-tPA in countries would be useful for

patients. This is also true in high-income countries. In Switzer-

land, for example, admission to hospitals not offering thromboly-

sis was as often the exclusion for IV-tPA use as other established

medical exclusion criteria (32).

IV-tPA for AIS is cost-effective where studied. In the original

National Institute of Neurological Disorders and Stroke (NINDS)

IV-tPA trial, 564 (95% CI 3 to 850) quality-adjusted life years

(QALYs) were estimated to be saved over 30 years per 1000 patients

(33). For each additional 2% of AIS patients treated with IV-tPA

each year, a savings of 7 million dollars annually would result (34).

A separate analysis from Canada estimated a lifetime savings of

3800 CDN and increase of QALYs by 3·46 per each patient treated

with IV-tPA (35). Although a small study in Thailand concluded

that the cost of IV-tPA for AIS was offset by improved outcome

based on modified Rankin scale score (36), studies of cost-

effectiveness of IV-tPA in LMIC are lacking (37). An analysis of

cost-effectiveness of IV-tPA for AIS in LMIC should consider the

infrastructure necessary to overcome the multiple barriers to

IV-tPA use in LMIC, including a strategy for rapidly transporting

patients to a facility; education of the public to recognize stroke

and present acutely to a health center; development of protocols

for diagnosis and management of stroke for non-neurologist phy-

sicians and other healthcare providers; acquisition and mainte-

nance of CT scanners; rapid access to radiologists; and adequate

monitoring capacity for a patient who has received IV-tPA

(6,20,21,24).All of these aspects of acute stroke care are essential to

acute stroke management even in the absence of IV-tPA; however,

it remains to be determined which interventions would be most

cost-effective in LMIC. Ongoing efforts in stroke prevention and

rehabilitation therefore remain paramount (5).

The strengths of this study include extensive review of multiple

databases, conference abstracts, and previous review articles to

assess the global reported use of IV-tPA for AIS. Analyses includ-

ing national level indicators reveal strong trends and patterns in

the reported use of IV-tPA. However, this study has several limi-

tations. It is possible that some countries using IV-tPA do not

report its use. Medical research and publication in indexed jour-

nals may be limited in low-income settings. One published survey

of healthcare workers to discern IV-tPA use for AIS has been

performed, but the response rate was limited (6). Studies of drug

sales and licensing by pharmaceutical companies could comple-

ment data published in medical journals but cannot be reliably

equated to drug use in a country and would not allow for the

determination of the indication of IV-tPA use for stroke vs. myo-

cardial infarction. Language of publication may limit the extent

of discovery by the authors of reports of IV-tPA use in some

languages; however, attempts to include all abstracts from

PubMed (MedLine) and Embase were made. Additional searches

of Spanish, French, Arabic, or Portuguese language databases may

have increased the number of countries reporting IV-tPA use if

performed in this study, although parallel searches in other data-

bases, such as African Index Medicus and Global Health, revealed

no additional countries reporting IV-tPA use compared with our

searches in PubMed (Medline) and Embase. Another notable

limitation is the combined reporting of AIS and hemorrhagic

stroke by the World Health Organization and Global Burden of

Disease program at the country level in 2004. Given limitations

of reporting globally, our models that include measurements of

DALYs and mortality from stroke necessarily combined both isch-

emic and hemorrhagic stroke sub-types. Finally, we did not

address the use of urokinase or streptokinase for AIS treatment,

which occurs in some LMIC countries.

In recent years, the growing burden of stroke in low- and

middle-income countries has become increasingly apparent (38).

Similar to what we have described for IV-tPA, use of stroke pre-

vention therapies is also related to a country’s income level and

per capita health expenditure (15). This creates a double burden

of lack of access to both acute and preventive treatments for

patients with stroke. We set out to understand the extent to which

acute stroke therapy with IV-tPA is reported, as this may serve as

a potential indicator of access to the most advanced acute stroke

care worldwide. Further research must identify barriers to acute

stroke treatment that can be studied and ultimately overcome.

Initiatives to improve acute stroke care should proceed in parallel

with ongoing efforts in stroke prevention and rehabilitation.

References1 Lozano R, Naghavi M, Foreman K et al. Global and regional mortality

from 235 causes of death for 20 age groups in 1990 and 2010: asystematic analysis for the Global Burden of Disease Study 2010.Lancet 2012; 380:2095–128.



354 Vol 9, April 2014, 349–355

2 Murray CJ, Vos T, Lozano R et al. Disability-adjusted life years(DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: asystematic analysis for the Global Burden of Disease Study 2010.Lancet 2012; 380:2197–223.

3 Feigin VL. Stroke in developing countries: can the epidemic bestopped and outcomes improved. Lancet Neurol 2007; 6:94–7.

4 No authors listed. Tissue plasminogen activator for acute ischemicstroke. The National Institute of Neurological Disorders and Strokert-PA Stroke Study Group. N Engl J Med 1995; 333:1581–7.

5 Strong K, Mathers C, Bonita R. Preventing stroke: saving lives aroundthe world. Lancet 2007; 5:182–87.

6 Pandian JD, Padma V, Vijaya P, Sylaja PN, Murthy JMK. Strokeand thrombolysis in developing countries. Int J Stroke 2007;2:17–26.

7 Barber M, Langhorne P, Stott DJ. Barriers to delivery of thrombolysisfor acute stroke. Age Ageing 2004; 33:94–5.

8 Eissa A, Krass I, Bajorek BV. Barriers to the utilization of thrombolysisfor acute ischemic stroke. J Clin Pharm Ther 2012; 37:399–409.

9 Ghandehari K. Barriers of thrombolysis therapy in developingcountries. Stroke Res Treat 2011; 2011:686797.

10 Engelter ST, Gostynski M, Papa S, Ajdacic-Gross V, Lyrer PA. Barriersto stroke thrombolysis in a geographically defined population.Cerebrovasc Dis 2007; 23:211–5.

11 World Bank. Data: how we classify countries. Available at http://data.worldbank.org/about/country-classifications (accessed 16 Febru-ary 2013).

12 World Health Organization. Data and statistics: countries. Available athttp://www.who.int/countries/en/ (accessed 16 February 2013).

13 World Health Organization. Department of Measurement and HealthInformation.Global burden of disease. Available at http://www.who.int/healthinfo/global_burden_disease/gbddeathdalycountryestimates2004.xls ( accessed 16 February 2013).

14 Stroup DF, Berlin JA, Morton SC et al. Meta-analysis of observationalstudies in epidemiology: a proposal for reporting Meta-analysis ofObservational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12.

15 Yusuf S, Islam S, Chow CK et al. Use of secondary prevention drugsfor cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospectiveepidemiological survey. Lancet 2011; 378:1231–43.

16 Schmülling S, Grond M, Jobst R, Heiss W. One-year follow-up in acutestroke patients treated with rtPA in clinical routine. Stroke 2000;30:1552–4.

17 Schneider AT, Pancioli AM, Khoury JC et al. Trends in communityknowledge of the warning signs and risk factors for stroke. JAMA2003; 289:343–46.

18 Langhorne P, de Villiers L, Pandian JD. Applicability of stroke-unitcare to low-income and middle-income countries. Lancet Neurol 2012;11:341–8.

19 Müller-Barna P, Schwamm LH, Haberl RL. Telestroke increases use ofacute stroke therapy. Curr Opin Neurol 2012; 25:5–10.

20 Ghandehari K, Foroughipour M, Pourzahed A et al. Thrombolysisin stroke patients: problems and limitations. Iran J Med Sci 2010;35:145–8.

21 Pandian JD, Sethi V, Dhillon R et al. Is intravenous thrombolysisfeasible in a developing country. Cerebrovas Dis 2005; 20:134–6.

22 Nandigam K, Narayan SK, Elangovan S, Dutta TK, Sethuraman KR,Das AK. Feasibility of acute thrombolytic therapy for stroke. NeurolIndia 2003; 51:470–3.

23 Pandian JD, Srikanth V, Read SJ, Thrift AG. Poverty and stroke inIndia: a time to act. Stroke 2007; 38:3063–9.

24 Wassay M, Barohi H, Malik A, Yousuf A, Awan S, Kamal AK.Utilization and outcome of thrombolytic therapy for acute stroke inPakistan. Neurol Sci 2010; 31:223–5.

25 Nguyen TH, Truong AT, Ngo MB et al. Intravenous thrombolysis.Int J Stroke 2010; 5:514–8.

26 Guinhouya KM, Tall A, Kombate D et al. [Cost of stroke in Lomé(Togo).]. Sante 2010; Aug. 4, PMID: 20682484.

27 World Health Organization & World Federation of Neurology. Atlas:Country Resources for Neurological Disorders. Geneva, World HealthOrganization, 2004.

28 El Khamlichi A. African neurosurgery: current situation, priorities,and needs. Neurosurgery 2001; 48:1344–7.

29 Brainin M, Teuschl Y, Kalra L. Acute treatment and long-termmanagement of stroke in developing countries. Lancet Neurol 2007;6:553–61.

30 Akinyemi RO, Ogah OS, Ogunidpe RF et al. Knowledge and percep-tion of stroke amongst hospital workers in an African community.Eur J Neurol 2009; 16:998–1003.

31 Mateen FJ, Carone M, Alam N, Streatfield PK, Black RE. A population-based case-control study of 1250 stroke deaths in rural Bangladesh.Eur J Neurol 2012; 19:999–1006.

32 Engelter ST, Gostynski M, Papa S, Ajdacic-Gross-V LPA. Barriers tostroke thrombolysis in a geographically defined population. Cerebro-vasc Dis 2007; 23:211–5.

33 Fagan SC, Morgenstern LB, Petitta A et al. Cost-effectiveness of tissueplasminogen activator for acute ischemic stroke. NINDS rt-PA strokestudy group. Neurology 1998; 50:883–90.

34 Demaerschalk BM, Yip TR. Economic benefit of increasing utilizationof intravenous tissue plasminogen activator for acute ischemic strokein the United States. Stroke 2005; 36:2500–3.

35 Sinclair SE, Frighetto L, Loewen PS et al. Cost-utility analysis of tissueplasminogen activator therapy for acute ischaemic stroke: a Canadianhealthcare perspective. Pharmacoeconomics 2001; 19:927–36.

36 Chaisam T, Suwanwela NC, Phanthumchinda K. Cost-effectiveness ofrecombinant tissue plasminogen activator for acute ischemic stroke[abstract]. Abstracts of the 6th World Stroke Congress and Xth Inter-national Symposium on Thrombolysis and Acute Stroke Therapy,24–27 September 2008 Vienna, Austria and 21–23 September 2008,Budapest, Hungary. Int J Stroke 2008; 3(Suppl 1):267. P002–27.

37 Shahtaheri RA, Haghighi AB, Safari A, Cruz-Flores S. Recombinanttissue plasminogen activator (rtPA) and stroke unit for acute ischae-mic stroke in developing countries, are they cost-effective. Int J Stroke2012; 7:e9.

38 Feigin VL, Lawes CM, Bennett DA, Barker-Collo S, Parag V.Worldwide stroke incidence and early case fatality reported in 56population-based studies: a systematic review. Lancet Neurol 2009;8:355–69.



Vol 9, April 2014, 349–355 355

Documents

Worldwide reported use of IV tissue plasminogen activator for acute ischemic stroke