Standard strategies for acute ischemic stroke within the rtPA therapeutic window

On December 14, 1995, the New England Journal of Medicine published the results of the National Institute of Neurological Disorders and Stroke trial1 and suddenly neurologists from all over the world have started the war against stroke using IV recombinant tissue plasminogen activator (rtPA) within the first 3 hours of stroke onset as their first and strongest weapon against stroke.

Neurologists from the low- and middle-income countries like Brazil quickly realized the major challenges to implement this new treatment in their crowded emergency rooms that threaten delivery of timely care. One important suggestion for neurologists trained before the thrombolytic era is learning to work as a team during the acute care. First, neurologists need to evaluate the burden of stroke in their community and alert public health authorities to ensure that health, social care, and employment services are working together for the benefit of stroke victims, especially in countries with large socioeconomic inequalities.

Noncommunicable diseases including stroke are emergent conditions in low- and middle-income countries due to influence of socioeconomic determinants in the epidemiologic transition process. Countries like the BRICS group (Brazil, Russia, India, China, and South Africa) have among the highest stroke mortality rates and socioeconomic disparities in the world. Health authorities in these countries may identify their Stroke Belt regions measuring the magnitude of socioeconomic inequalities in a geographically defined population (state, city, or borough). This strategy will not only allow to locate resources in regions where the burden of stroke is disproportionately elevated, but also will ultimately help to break major barriers to universal health care access. The most striking example of this situation is seen in the figure, where a simple wall divides 2 contrasting communities living next to each other in São Paulo with different stroke risk profiles and unequal access to the health care system.

Socioeconomic differences in São Paulo, Brazil

Figure. Sao Paulo, Brazil, 2005. The Paraisópolis favela (Paradise City shantytown) borders the affluent district of Morumbi in São Paulo, Brazil (Photo: Tuca Vieira).

Epidemiologic studies demonstrating the burden of stroke in low- and middle-income countries are rare. Therefore, the stroke awareness campaigns should first be directed to the health authorities and hospital administrators to alert them to the economic burden of stroke in their community. At the same time, neurologists should report the burden of stroke in their emergency rooms, reviewing major stroke outcome indicators and treatment costs. Two publications demonstrated not only the substantial acute stroke treatment costs in Brazil, largely related to hospital complications, but also confirmed the cost-effectiveness of using IV rtPA in the acute setting of the Brazilian health care system.2,3

Brazilian neurologists started to improve training programs in acute stroke care before the approval of IV rtPA treatment in the United States. A few neurologists began to introduce the time window concept in their neurologic services. One of the earliest experiences came from a small acute stroke protocol developed at Albert Einstein Hospital in São Paulo and based on the ongoing similar trials running at that time in the United States. Only those patients with a documented intracranial arterial occlusion were included and the authors did not find major safety concerns in the first 6 patients treated.4 However, the protocol was stopped due to uncertainties observed by the hospital neurologists regarding this timely oriented “hazard approach.”

After Food and Drug Administration approval in the United States, the use of IV rtPA for acute ischemic stroke became the cornerstone of the stroke centers movement in Brazil. Neurologists started to build a Brazilian Stroke Network with the help of the Brazilian Academy of Neurology to provide educational programs and guidelines for organizing stroke centers. However, this highly skilled group has not equalized the stroke treatment performed in their communities. Gains in knowledge have not reached clinical practice and physicians at the same time during those years. Not only was awareness of stroke symptoms low, but emergency services were not prepared for treating these patients, delaying access to acute stroke care.5

Several years later, IV rtPA treatment was approved by the Brazilian Ministry of Health for acute ischemic stroke patients. This was an important step to support neurologists in their battle for the recognition of IV rtPA effectiveness in acute ischemic stroke. Soon after, the Brazilian Academy of Neurology published 2 guidelines, one for acute stroke management and the other for specific use of thrombolytic therapy.6,7 Although the proportion of ischemic stroke patients receiving IV rtPA has improved, reaching in some regions 13.7%,8 the overall IV rtPA stroke treatment in the country remained very low.

The socioeconomic disparities in stroke treatment are largely influenced by the level of education of the target population. Lower level of education prevents patients from identifying major stroke warning signs and calling the national emergency medical service number (192).9 The World Stroke Organization together with regional and national Stroke Societies has helped to improve stroke awareness in the Latin American region. The National Campaign for the World Stroke Day in Brazil has included many supporters throughout the country during recent years. Recently, the World Stroke Congress in Brasilia has definitively amalgamated Brazil and Latin America within the World Stroke Organization to strengthen its fight against stroke in the region.

Aging of the population is another concern, not only in the developed world, but also in low- and middle-income countries, where elderly are the fastest growing population. One of the major advances in the prior Brazilian Guidelines was the inclusion of elderly patients as a special category with warning considerations to receive IV rtPA.6,7 Stroke patients 80 years or older were allowed to receive the treatment under restricted conditions. This approach facilitated early access of the elderly population to thrombolytic treatment in Brazil. This was confirmed in a recent publication, where a significant proportion of elderly stroke patients received IV rtPA in a major Brazilian metropolitan area.8

In recent years, Brazilian acute stroke patients have been evaluated in primary and comprehensive stroke centers and offered advanced treatment.9 The Joint Commission has certified primary stroke centers in Brazil and recently the acute stroke guidelines from the Brazilian Academy of Neurology has also extended the use of IV rtPA up to 4.5 hours from stroke onset.10 Neurointerventional procedures have increasingly been used in acute stroke patients in Brazil including mechanical thrombectomy with stent retrieval.11

One may question whether the low- and middle-income countries are following the right pathway to the future of acute stroke treatment, chasing the boundaries of the therapeutic window using thrombolytic therapy with sophisticated imaging protocols and expensive recanalization tools affordable for few individuals. Instead, maybe they would rather innovate breaking the walls between emergency rooms and patients. One way of doing that is improving prehospital care with telemedicine systems connecting mobile stroke units to comprehensive stroke centers located in strategic areas that would permit rapid access to all stroke patients regardless of socioeconomic status. These strategies might reduce the symptom-to-needle time, allowing a higher efficacy of IV rtPA treatment in large metropolitan areas, where the majority of the Brazilian population lives. In addition, it could offer advanced treatment to selected stroke patients with higher chances of success than presently found.

Finally, several studies have demonstrated that stroke mortality rates in Brazil have progressively declined in recent years.12 However, the number of stroke survivors with functional incapacity increased. The majority of stroke patients in Latin America are discharged directly home from acute care. The next battle against stroke in these countries will need to facilitate early access to rehabilitation centers for keeping and improving the favorable outcome obtained by the acute stroke treatment.

Correspondence to: ayrton.massaro@gmail.com