Monday, March 11, 2019

Thrombolysis, Thrombectomy and Acute Stroke Therapy. Series. Part 1

The World Stroke Organization will be publishing over the coming six weeks excerpts from experts on the latest in thrombolysis, thrombectomy and acute stroke therapy. In this blog session some of the most dynamic researchers in stroke will be exploring strokes changing demographics, global rates of thrombectomy, and how current treatments have changed the stroke landscape in this area. A summary of this meeting, and an extended report are available in the International Journal of Stroke, the flagship publication of the World Stroke Organization.  

The objectives of TTST 2018 were to explore the changing landscape of acute ischemic stroke therapy and to address current controversies in thrombolysis and thrombectomy. With the goal of reaching a consensus on how these therapies will evolve over the next several years, data of the relevant neuroscience were presented by experts of the field. Importantly, the emphasis was not only on scientific advances, but also on expanding access by a focus on systems of care with global relevance. Presentation of already published data was discouraged. Invitees were selected to represent all specialties and regions involved in thrombolysis and thrombectomy. The format was a series of 3 or 4 talks on a general topic followed by an open discussion. Each talk was presented by a group of 3 experts and limited to 20 minutes. Another group of 3 or 4 experts led the subsequent discussion, aimed at encouraging frank and open debate among all attendees. This manuscript summarizes the proceedings of TTST 2018.  

Changing demographics of stroke and impact on thrombolysis and thrombectomy 

Global incidence of stroke and projected future trends

Dominique A. Cadilhac, George Howard, Anthony Kim

Annually, stroke is estimated to affect 15 million people worldwide, and is the third leading cause of disease burden.1In low and middle income countries (LMIC), 94% of deaths from stroke occur in people aged 2A clear understanding of disease trends around the world is important. In the latest systematic review by Thrift and colleagues3, it was confirmed that large geographical variations in stroke incidence and mortality still persist, with the largest burden observed in Eastern European countries and China. However, data are lacking from many countries, making the worldwide assessment of the burden of stroke challenging.  The Global Burden of Disease study has partially addressed this gap by providing estimates of the stroke burden in almost all countries. The estimates are derived by using evidence from the literature and modeling techniques to estimate stroke burden in countries with limited epidemiological information that is overseen by an expert group from 41 countries.4,5
Although there is evidence that stroke incidence rates have declined, and prevalence rates have remained similar. Between 1990 and 2016 the absolute number of stroke survivors has almost doubled, and it is estimated that currently there are over 80 million people living with stroke (unpublished, Feigin 2018). Of great concern is that over 60% of people living with stroke are younger than 70 years. In HIC like Australia, about 1 in 4 strokes now affects people aged 18-64 years, impacting their ability to work and their role in society.6However, the burden of stroke at lower ages is much larger in LMIC where stroke affects people at a younger age and where overall life expectancy is lower. In terms of disability and deaths, the greatest burden currently resides in developing countries, and the gap between developed and developing countries is increasing.4Increasing life expectancy and population growth explain some of these trends which are compounded by a global epidemic of people with metabolic risk factors such as obesity, type 2 diabetes, and hypertension,4which are important risk factors for stroke.5
These changes in the burden of disease from stroke are the result of demographics shifts, as well as health sector and non-health sector trends. Population growth, particularly in the developing world, as well as aging, particularly in upper income and middle-income countries, both contribute to the increasing absolute stroke burden expected in the coming years.7Trends in risk factors, such as hypertension, and the expected impact of both favorable and unfavorable trends vary across countries, with unfavorable trends in blood pressure and obesity in China and Brazil for instance, as compared to generally favorable trends in blood pressure and cholesterol in many developed countries, but not obesity.5The net impact of these factors is a substantial increase in the relative age-standardized burden of stroke in the developing world. While many developed countries continue to show improvement of long-term trends, a significant increase in the absolute burden of stroke is expected with any potential improvements in incident events been outweighed by demographic shifts.1
In the US, the absolute age-adjusted mortality rate for stroke has potentially plateaued after decades of decline. Coupled with the continued “greying of America” where the population will continue to age in the coming decades, with a considerable growth in the oldest of the old (age > 85), which will double from 5% to 10% of the population. There are accompanying changes in the race/ethnic distribution of the aged as well (Figure 1).6A forecasting model that combines estimates of population growth, assumed stroke incidence rates by age, sex, and race/ethnicity, predicts substantial shifts in the distribution of stroke events over the next 40 years. A more than doubling of the total number of stroke events is expected, with nearly all of this increase in the elderly where the proportion of strokes occurring at ages 75 and older increased from 50% in 2010 to 61% in 2050. Projected changes will also have an impact on the race/ethnic distribution of stroke events with a decrease in the proportion of strokes that occur in whites from 75% to 56%, and an increase in Hispanics from 11% to 24%. These forecasts justify the need to expand capacity to treat patients with stroke, to refine interventions and therapies to the elderly population, and to focus on stroke care for minority populations in the future. We also need to ensure capacity building in LMIC countries to support efforts in the prevention and treatment of stroke, and overall, encourage routine and standardized data collection for better capturing the burden of stroke around the world.

Global rates of thrombolysis and thrombectomy

Dawn Kleindorfer, Werner Hacke, Kazunori Toyoda

Over the past decade, thrombolysis rates have increased particularly in a subset of patients arriving within 2 hours from time of symptom onset. Overall use of intravenous alteplase in patients, without regarding time of arrival or contraindications for alteplase administration, has remained similar.8Utilization rate in centers located in urban communities has increased but rural areas don’t exhibit the same pattern. After the publication of pivotal randomized controlled trials, mechanical thrombectomy rates increased significantly in patients arriving up to 4.5 hours after symptom onset with an NIHSS > 5; additionally there was a significant 7% increase in thrombectomy in all stroke patients, despite the fact that almost two-thirds of patients arrive in the late time window.9In Germany thrombolysis increased to 13.5% and thrombectomy to 4.5% in 2016; although mechanical embolectomy increased at a lower rate in rural areas. The far majority of patients are being treated in high-volume centers with more than 25 cases/year and more than 50% were treated in centers with over 100 patients/year.10Asia exhibits very low thrombolysis and thrombectomy rates when compared to each individual country’s population, as presented by Kazunori Toyoda, MD by verbal communication. Access to thrombolysis and thrombectomy centers, along with patient eligibility at the time of hospital arrival may account for this trend. 

Changing stroke demographics and characteristics as a result of preventive interventions and impact on thrombolysis and thrombectomy with focus on atrial fibrillation and large veseel occlusion vs non-large vessel occlusion stroke

Phil Bath, Mitchell S. V. Elkind, Hooman Kamel

The concept of the “epidemiologic transition” has been used to explain the shift in the relative proportions of diseases that may occur in countries as they experience different stages of socioeconomic development.11Epidemiologists have described at least five stages of transition.  In the first stage, pestilence and famine, nutritional deficiencies and infections dominate; in the world of stroke, Chagas disease could occur, for example. The second stage is characterized by diseases related to hypertension, such as hemorrhagic and small vessel strokes, and includes large parts of Asia, including China.  In the third stage, degenerative and man-made diseases, high fat diets, sedentary lifestyles, and cigarette smoking allow chronic, degenerative, and “man-made” diseases, including cardiovascular disease and ischemic stroke, to become more prominent, as in urban India. In the fourth stage, delayed degenerative disorders, there are increased efforts to prevent, diagnose, and treat these lifestyle-related diseases, which allows for a delay in their age of onset as well as the increase in degenerative diseases affecting the elderly. Western Europe and North America are considered to be in this fourth stage of the epidemiologic transition. At this stage, we might expect an increase in large vessel occlusions due to atrial fibrillation and other sources of cardioembolic stroke, as well as effects of large artery atherosclerosis, amyloid angiopathy, and vascular dementia. Finally, a fifth stage of societal upheaval and social regression may exist in which existing health structures break down, leading to a resurgence of conditions seen in the first two stages, as well as to the effects of violence and accidents (parts of post-Soviet Russia has been suggested as an example). Here, vascular neurologists and stroke physicians would encounter traumatic hemorrhages of many types.

Empirical evidence of the epidemiologic transition in relation to stroke was well described in the Sino-MONICA-Beijing project.12In this community-based surveillance study, there were temporal trends in stroke incidence and subtype in Beijing over only two decades of rapid economic development, from 1984 to 2004. Four characteristics of the epidemiological transition were observed: declining incidence of hemorrhagic stroke due to improved treatment of hypertension, reduced case fatality due to improved treatment after stroke, increased age of stroke onset, and an expanded proportion of ischemic heart disease deaths with a decreased proportion of stroke deaths in the study population. Additionally, an increase in the incidence of ischemic stroke was found which was felt to be secondary to increased atherosclerotic risk factors. Though not a particular focus of this analysis, it is likely that cardioembolic stroke related to the aging of the stroke population and the increase in ischemic heart disease in particular, and thus large vessel occlusion, would be part of this picture. 

Of course, the epidemiologic transition is not limited to the developing world, and disparities are reflected within all nations. In the United States (US), racial minorities suffer increased stroke mortality and disability rates compared to non-Hispanic whites. African Americans have the highest mortality rates due to stroke and Hispanics have a higher stroke incidence than Whites. In the southeastern US, within a region referred to as the “Stroke Belt”, stroke mortality and incidence rates are increased. The highest rates are found along the coast, in Georgia and North and South Carolina, in a region nicknamed the “Stroke Buckle”.  Variations in race or ethnicity of people comprising the population do not appear to fully explain the disparities in stroke mortality and incidence that exist in the southeastern US, since African-Americans in the Stroke Belt have increased stroke risks compared to those in other parts of the country.13The difference may be attributable to socioeconomic factors limiting access to care, producing an increase in the prevalence of stroke risk factors.14In an analysis of the National Health and Nutrition Examination Survey, moreover, there is evidence that despite improving trends in the burden of cardiovascular risk factors among high-income individuals in the US, low-income populations are not sharing these favorable trends.15Thus, while there have been improvements in the control of risk factors for cardiovascular disease in the US, it remains unclear that all socioeconomic strata have benefited equally, and as the population grows, we can expect more large vessel occlusion (LVO) stroke to occur. 

In this context, it is also important to ask if there are differences in the risk of LVO by sex or race/ethnicity. The two major stroke mechanisms leading to LVO are cardiac embolism and large-artery atherosclerosis. Although there is less atrial fibrillation (AF), the most common cardioembolic risk factor in women when adjusting for age,16this issue is less relevant at the time of stroke presentation since women generally present with stroke at a later age. In support of this, there was an essentially even distribution of men and women in trials of mechanical thrombectomy or other acute stroke therapies.17There are race/ethnicity-related differences in ischemic stroke subtypes, with Caucasians having a greater risk of cardioembolic stroke and Asians a higher risk of large-artery atherosclerosis.18However, given the contribution of large-artery atherosclerosis and cardiac embolism to LVO, there appears to be no race/ethnic differences in LVO risk.19

Discussion Panel

Joe Broderick, Devin Brown, Nicole Gonzales, Anjail Sharrief 

With aging of the population and changes in racial demographics in the US, we expect an increased number of strokes in Hispanics, elderly, and females in the coming years and we need to be prepared for this. These changes raise a number of questions. Will we see an increase in patients with cardioembolic stroke requiring a greater demand for endovascular therapy (EVT)? Are we prepared? Do we have the interventionalists situated in the right regions? Currently rural areas are largely underserved. On the other hand, understanding the ‘denominator’ helps to determine which patient population we are going to shift resources towards. The reality is that the percentage of patients eligible for EVT, while growing, is still small. We also need to be prepared to offer treatment to a larger proportion of elderly patients. 

On a global level, there are very limited data in lower income countries where incidence of stroke is increasing. For these countries, the best use of resources may be in prevention. We should not exclude the possibility that some countries may have resources to provide thrombolytic therapy and we should support these countries in establishing stroke centers; however, setting up endovascular labs and advanced imaging does not seem plausible and the public health benefit of EVT much more limited. Even in the US, despite the exciting advances in endovascular treatment, the biggest public health benefits are still in prevention. Finally, it important for us to see input from physicians in lower income countries to determine the type of support that it is needed.

Key Points: 

  1.  Stroke incidence forecasting models predict a more than doubling of the total number of stroke events, with nearly all of this increase in the elderly. The racial profile of stroke patients will also rapidly change in the next decade. These forecasts justify the need to expand capacity and treatment of the elderly and minorities.
  2. While there have been improvements in the control of risk factors for cardiovascular disease in the US, it remains unclear that all socioeconomic strata have benefited equally, and as the population grows, we can expect more LVO to occur.
  3. At present, thrombolysis and thrombectomy rates around the world remain low relative to the clinical burden of stroke. This disparity raises serious questions as to our preparedness for the forecasted increased stroke numbers, and suggests a redoubling of efforts aimed at prevention.

1. Thrift AG, Thayabaranathan T, Howard G, Howard VJ, Rothwell PM, Feigin VL, Norrving B, Donnan GA, Cadilhac DA. Global stroke statistics:. International Journal of Stroke. 2017;12:13–32. 
2. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, Barker-Collo S, Moran AE, Sacco RL, Truelsen T, Davis S, Pandian JD, Naghavi M, Forouzanfar MH, Nguyen G, Johnson CO, Vos T, Meretoja A, Murray CJL, Roth GA, GBD 2013 Writing Group, GBD 2013 Stroke Panel Experts Group. Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015;45:161–176. 
3. Feigin VL, Norrving B, Mensah GA. Global Burden of Stroke. Circ. Res.2017;120:439–448. 
4. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJL. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372:1333–1341. 
5. Kim AS, Cahill E, Cheng NT. Global Stroke Belt: Geographic Variation in Stroke Burden Worldwide. Stroke. 2015;46:3564–3570. 
6. Howard G, Goff DC. Population shifts and the future of stroke: forecasts of the future burden of stroke. Ann. N. Y. Acad. Sci.2012;1268:14–20. 
7. Scott PA, Temovsky CJ, Lawrence K, Gudaitis E, Lowell MJ. Analysis of Canadian population with potential geographic access to intravenous thrombolysis for acute ischemic stroke. Stroke. 1998;29:2304–2310. 
8. Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, Bhatt DL, Grau-Sepulveda MV, Peterson ED, Fonarow GC. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6:543–549. 
9. Smith EE, Saver JL, Cox M, Liang L, Matsouaka R, Xian Y, Bhatt DL, Fonarow GC, Schwamm LH. Increase in Endovascular Therapy in Get With The Guidelines-Stroke After the Publication of Pivotal Trials. Circulation. 2017;136:2303–2310. 
10. Bartig D, Kitzrow M, Brassel F, Busch EW, Nolden-Koch M, Reimann G, Weimar C, Weber R, Eyding J. Verfügbarkeit der mechanischen Thrombektomie bei akutem Hirninfarkt. Der Nervenarzt. 2017;88:1–9. 
11. Yusuf S, Reddy S, Ôunpuu S, Circulation SA, 2001. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. 
12. Zhao D, Liu J, Wang W, Zeng Z, Cheng J, Liu J, Sun J, Wu Z. Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke. 2008;39:1668–1674. 
13. CDC. Stroke Hospitalization Rates, 2013-2015 Adult Medicare Beneficiaries, Ages 65+, by County. 2018;:1–1. 
14. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. The Lancet Neurology. 2009;8:345–354. 
15. Odutayo A, Gill P, Shepherd S, Akingbade A, Hopewell S, Tennankore K, Hunn BH, Emdin CA. Income Disparities in Absolute Cardiovascular Risk and Cardiovascular Risk Factors in the United States, 1999-2014. JAMA Cardiol. 2017;2:782–790. 
16. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim Y-H, McAnulty JH Jr, Zheng Z-J, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJL. Worldwide Epidemiology of Atrial Fibrillation. Circulation. 2014;129:837–847. 
17.  Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, Dávalos A, Majoie CBLM, van der Lugt A, de Miquel MA, Donnan GA, Roos YBWEM, Bonafe A, Jahan R, Diener H-C, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millán M, Davis SM, Roy D, Thornton J, Román LS, Ribó M, Beumer D, Stouch B, Brown S, Campbell BCV, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.The Lancet. 2016;387:1723–1731. 
18. Ornello R, Degan D, Tiseo C, Di Carmine C, Perciballi L, Pistoia F, Carolei A, Sacco S. Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes. Stroke. 2018;49:814–819. 
19. Noorian AR, Sanossian N, Shkirkova K, Liebeskind DS, Eckstein M, Stratton SJ, Pratt FD, Conwit R, Chatfield F, Sharma LK, Restrepo L, Valdes-Sueiras M, Kim-Tenser M, Starkman S, Saver JL. Los Angeles Motor Scale to Identify Large Vessel Occlusion. Stroke. 2018;49:565–572. 

About: International symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy 
The 14thInternational Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy (TTST) took place in Houston, Texas on October 21stand 22nd, 2018. TTST meetings began in 1990 during the initial simultaneous clinical investigations into thrombolysis taking place in the United States, Europe, and Japan. Since then, TTST has brought together invited experts on reperfusion therapy for acute stroke every two years, and rotates among venues in Europe, North America, and Asia. TTST has provided opportunities for stimulating controversial discussions on data from recent clinical trials, the status of major ongoing studies, and priorities for future research. Initially focused on thrombolytic therapy, recent TTST conferences have helped lay the groundwork for the success of thrombectomy clinical research.  

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