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Alzheimer’s Disease: Prevention is the Best Treatment

Alzheimer’s disease (AD) is a progressive neurodegenerative condition and the most common cause of dementia. It accounts for about 60-80 % of all cases of dementia1. There are currently no curative or prevention therapies available for the disease. Medications prescribed for Alzheimer’s disease (AD) symptoms can temporarily help individuals with thinking, memory, or speaking skills and can help with some of the behavioral and personality changes associated with AD.  everal lines of evidence indicate that lifestyle habits and genetic factors play an important role in determining a person’s risk of developing AD2.

There have been a few recent disappointments with AD therapies when Biogen and Esai released negative results from a promising drug trial (3) and then Novartis, Amgen and Banner Alzheimer’s Institute announced in July their decision to not pursue further studies with a potential AD drug4. But new research presented at the Alzheimer’s Association International conference held in July at Los Angeles has provided evidence of a potential preventive strategy. Results from this study indicate that certain healthy lifestyle habits can reduce the risk of developing AD and even overcome the genetic risk in some susceptible individuals5.

During this retrospective cohort study,196 383 individuals aged at least 60 years, without evidence of cognitive impairment or dementia at baseline were followed for a median of 8 years. Risk assessment was performed using lifestyle and genetic risk scores. Lifestyle risk score was determined by a combination of smoking status, alcohol consumption, physical activity, and dietary habits. During the follow up period, a total of 1769 patients were diagnosed with new onset dementia. The incidence of dementia was noted in 1.23% of the high genetic risk group as compared to 0.63% in the low genetic risk cohort. The genetic risk was seen to be independent of the lifestyle factors.

About 68% participants followed a favorable lifestyle and 8% were noted to have an unfavorable lifestyle.

Dementia risk was seen to increase with worsening of lifestyle scores in a linear fashion. In the unfavorable lifestyle group, 1.16% persons developed dementia while 0.82% in the healthy lifestyle were diagnosed. Favorable lifestyle was associated with a lower risk of dementia despite an unfavorable genetic risk profile.

Favorable lifestyle habits in this study included: no smoking, limiting alcohol consumption to moderate levels, regular physical activity and maintaining a healthy diet. Regular physical activity was defined as per the American Heart Association (AHA) guidelines: 150 minutes of moderate or 75 minutes of vigorous activity per week (or an equivalent combination). This level of exercise, along with a healthy lifestyle, has also been associated with lowered risk of stroke and cardiovascular disease. Moderate alcohol consumption was defined according to the US dietary guidelines: 14g/day or less for women and 28g/day or less for men. Healthy diet was based on the dietary recommendations for maintaining optimal cardiometabolic health: this included regular consumption of at least 4 of the 7 food groups which constitute a healthy diet6.

This study provides evidence to support the benefits of a healthy lifestyle in reducing risk of dementia, even in individuals who may be at a higher genetic risk of developing dementia, including AD.  These results reinforce the American Heart Association’s healthy lifestyle recommendations for a healthy heart and healthy brain.

 

References:

  1. https://www.alz.org/alzheimers-dementia/what-is-dementia
  2. MangialascheF,KivipeltoM,SolomonA, Fratiglioni L. Dementia prevention: current epidemiological evidence and future perspective. Alzheimers Res Ther. 2012;4(1)
  3. http://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials
  4. https://www.novartis.com/stories/discovery/stopping-alzheimers-disease-it-starts
  5. Ilianna Lourida, PhD1,2; Eilis Hannon, PhD1; Thomas J. Littlejohns, PhD3; et al. Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA. Published online, July 13, 2019.
  6. Dietaryandpolicyprioritiesfor cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation. 2016;133(2): 187-225
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To RESTART or Not to RESTART- That is The Question

During the European Stroke Organization conference, clinical trial results were presented, including investigation of treatments and outcomes of both ischemic and hemorrhagic stroke.

One of the most remarkable and surprising results were from the RESTART trial1 presented by Professor Rustam Al-Shahi Salman (Twitter @BleedingStroke) from the University of Edinburgh. This randomized open label trial was designed to answer the question whether antiplatelet medications can be safely restarted in patients who survive a recent intracerebral hemorrhage. The study participants were enrolled from 122 hospitals in the UK and included adults who had developed an intracerebral hemorrhage while on an antithrombotic medication for prevention of ischemic vascular disease.1 A total of 537 patients were randomly assigned to either restart or continue to avoid antiplatelet medication and followed for a median of 2 years for a primary outcome of recurrent symptomatic intracerebral hemorrhage.  In the group assigned to restarting antiplatelet medications, 12 of 268 subjects experienced recurrent intracerebral hemorrhage as compared to 23 of 268 in the group assigned to avoid antiplatelets (p=0.06).1 The rates of all major hemorrhage events in the two groups were similar: 7% in the treatment group and 9% in the avoiding group (p=0.27). There was no difference in the rates of occlusive vascular events which were seen at 15% in the treatment group and 14% in the avoiding group (p=0.92).1

Prior evidence suggests that aspirin is beneficial for secondary prevention of ischemic vascular events, notwithstanding a small increase in the risk of intracerebral hemorrhage2. RESTART is the first RCT studying the effects of restarting aspirin in patients with a prior history of ischemic vascular disease and a recent intracerebral hemorrhage. While not statistically significant, the results demonstrate a lower rate of recurrent hemorrhage if antiplatelet medications are resumed for prevention of occlusive vascular disease despite a recent intracerebral hemorrhage. The composite secondary outcome of non-fatal MI, non-fatal stroke or death from a vascular cause was seen at a significantly lower rate in the treatment group (p=0.025) as compared to the antiplatelet avoiding group.2

The reduced risk of recurrent hemorrhage risk is a surprising finding and needs further confirmation. The authors postulate that this can be potentially explained by shared mechanistic pathways between ischemic stroke and intracerebral hemorrhage.

The results from this trial provide reassurance that antiplatelet medications can be safely restarted for secondary ischemic event prophylaxis in patients with a recent intracerebral hemorrhage. There are ongoing clinical trials including RESTART-Fr3 and STAT ICH4 and the results from these would provide more insight into the effects of antiplatelet therapy resumption after an intracerebral hemorrhage.

 

References:

  1. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019 May 21. RESTART Collaboration.
  2. Antithrombotic Trialists’ (ATT) Collaboration Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373: 1849-1860. Baigent C, Blackwell L et al.
  3. https://clinicaltrials.gov/ct2/show/NCT02966119
  4. https://clinicaltrials.gov/ct2/show/NCT03186729
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The Pursuit of Gender Equality: A WISE Idea

Each year, the second Sunday of May is observed as Mother’s Day. This day provides an opportunity to celebrate and honor the mothers in our lives. Mothers make many sacrifices to ensure that their kids lead healthy and successful lives. They continually strive to balance their family and professional responsibilities. Women often put their careers on hold in order to raise their families. Even though there has been some improvement in recognition of gender bias issues inside workplaces, women are more likely to face family related interruptions in their careers1. This social construct along with the culture of bias and discrimination in the workplace has led to women being grossly underrepresented in positions of leadership and influence, healthcare being no exception to this phenomenon. Lower salaries, a work culture that favors men, and sexual harassment are some grave challenges that women encounter in their professional lives. There has been a growing awareness of this problem in the last few years, thanks to efforts lead by organizations such as TIME’S UP.

Within the field of academic Neurology, there has been a growing call to recognize these issues related to gender disparity2. Women are underrepresented both as recruited subjects in neurological clinical trials and also as project leaders for those clinical trials. A recent observational study found that only about 31% of all academic Neurology positions are held by women; this disparity widens as the academic rank increases with only 13.8% of Neurology professors being women3. Men also appear to have a higher rate of academic publications than women, with larger gaps seen at junior faculty positions. Similar gender inequities have been noted in other specialties including neurosurgery, orthopedic surgery and radiology4. However, this disparity cannot be explained by a lack of female representation in medical schools. American Association of Medical Colleges data from 2017 revealed that female students accounted for 50.7% of all enrollees in medical schools, which is a 9.6% increase since 20155.

Similar to the business world, social media has played an important role in increasing recognition and reporting of gender disparities within the field of Neurology. Women Neurologists Group (WNG) was formed in 2015 as a closed Facebook group, which now has more than 2,000 members and also has more than 1,000 followers on Twitter (@WNGtweets). This group of “Women neurologists networking and supporting each other” provides a platform for women neurologists to discuss, among other topics, issues related to maintaining the family-work balance. According to Dr. Kathrin Lafaver (@LaFaverMD, Assistant Professor of Neurology at University of Louisville) who is one of the founding members of the group, this forum has provided a safe space for women to share their experiences and opinions about a variety of subjects including the problem of gender disparity and it’s potential solutions6. The American Academy of Neurology set up a task force to study the underlying causes of gender disparity in the field and put forth recommendations to tackle this problem. As part of this initiative, the academy established a “Women leading in Neurology” program in 2017 which aims to help women neurologists gain the appropriate leadership skills to advance their careers and attain top tier positions within their field.

Gender disparity in healthcare is obviously not an issue unique to the United States and is becoming recognized around the world. Last year, the European Stroke Organization (ESO) established WISE (Women Initiative for Stroke in Europe), with its main goal of improving stroke care for women across Europe. The group aims to increase awareness about stroke risk factors and symptoms  in women and to ensure gender equity when it comes to stroke care in the continent. One of the objectives of the group is to support women clinicians and researchers in the field of stroke medicine and to help them attain leadership positions. The group organized their second annual WISE stroke leadership workshop earlier this week in conjunction with the ESO conference in Milan, Italy. During this workshop, Dr. Natalia Rost (@nsanar Professor of Neurology, Harvard University) represented the STROKE journal and provided a call for action to increase female leadership in the field of academic stroke neurology. She advocated for increased transparency within academic departments, recognizing achievements and contributions of women scientists and promoting diversity within scientific committees and editorial boards7. These are important steps toward establishing a culture of equality and fairness within the field of medicine.

While there is a clear commitment within neuroscience and the medical community at large to promote diversity inside academic and clinical arenas; a lot still needs to be done to help women maximize their potential as clinicians, educators and researchers. At this time of the year when we celebrate Mother’s day, let’s all pledge to support the women in our lives so that they can attain all the personal and professional success that they deserve.

 

References:

  1. https://www.pewresearch.org/fact-tank/2015/03/10/women-still-bear-heavier-load-than-men-balancing-work-family/
  2. Silver JK, Bank AM, Slocum CS, Blauwet CA, Bhatnagar S, Poorman JA, et al. Women physicians underrepresented in American Academy of Neurology recognition awards. Neurology. 2018;91:e603–e614
  3. McDermott M, Gelb DJ, Wilson K, Pawloski M, Burke JF, Shelgikar AV, et al. Sex differences in academic rank and publication rate at top- ranked US neurology programs. JAMA Neurol. 2018;75:956–961
  4. Jagsi, Reshma et al. Sex, Role Models, and Specialty Choices Among Graduates of US Medical Schools in 2006–2008. Journal of the American College of Surgeons , Volume 218 , Issue 3 , 345 – 352
  5. https://aamc-black.global.ssl.fastly.net/production/media/filer_public/5c/26/5c262575-52f9-4608-96d6-a78cdaa4b203/2017_applicant_and_matriculant_data_tables.pdf
  6. https://journals.lww.com/neurotodayonline/FullText/2018/07190/Neurologists_on_Social_Media__The_Women.13.aspx
  7. Charlotte Cordonnier, Shelagh B. Coutts, Karen C. Johnston, Natalia S. Rost. Crucial Role of Women’s Leadership in Academic Stroke Medicine You Can’t Be What You Can’t See. https://doi.org/10.1161/STROKEAHA.118.024788
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Embolic Stroke of Undetermined Source: Current State of Evidence

Approximately 30% of all ischemic strokes are caused by an unknown etiology, also sometimes referred to as cryptogenic stroke1. Cryptogenic stroke has been defined as a cerebral infarct without a clear attributable etiology despite extensive vascular, cardiac and laboratory evaluations2. The possible underlying mechanisms for these ischemic strokes are varied and may include occult paroxysmal atrial fibrillation, paradoxical embolism with a patent foramen ovale (PFO), hyper coagulable state, non stenotic atherosclerotic disease.

A more recently coined term has been used to describe cryptogenic strokes which appear embolic on brain imaging: Embolic Stroke of Undetermined Source (ESUS). ESUS accounts for more than half of all cryptogenic strokes and has been defined as a cortical infarct without ipsilateral proximal arterial stenosis or a cardio embolic source3. Antiplatelet medications are generally used to prevent recurrent stroke in the absence of atrial fibrillation. However, clinical studies with long term cardiac rhythm monitoring have demonstrated a higher prevalence of atrial fibrillation in the cryptogenic stroke population4,5. With this background two clinical trials were initiated to investigate whether the direct oral anticoagulants were more effective than aspirin for secondary stroke prevention in patients with ESUS.

Results from the RESPECT-ESUS were presented at the World Stroke Congress in October 20186. The trial showed similar stroke rates with the two drugs at 19 months follow up; 4.8% per year with aspirin and 4.1% per year with dabigatran ( p=0.1 HR=0.85). The major bleeding events occurred at a similar rate with the two drugs- 1.4% per year with aspirin and 1.7% per year with dabigatran. Even though these results did not show a statistically significant difference, there is a slight indication of benefit in favor of dabigatran when patients are followed for long term. A post hoc subgroup analysis showed a statistically significant reduction in secondary stroke rates with dabigatran among patients older than 75 years.

NAVIGATE-ESUS7 trial was designed to compare rivaroxaban 15mg/day to aspirin 100mg/day in patients with a recent ESUS event. This was a multi-national trial which enrolled about 7000 patients who were then followed for a median time of 11 months after randomization. The trial was terminated early due to an increased risk of bleeding associated with rivaroxaban without a significant benefit of stroke risk reduction. Recurrent stroke or systemic embolism occurred at 5.1%/year in the rivaroxaban group as compared to 4.8%/year in the aspirin group. In the rivaroxaban group, there were 13 hemorrhagic stroke events as compared to 2 in the aspirin group. Major bleeding rates were also higher in the rivaroxaban group: 1.8%/year vs. 0.7%/year with aspirin.

An exploratory subgroup analysis was subsequently performed and the results were published earlier this month in JAMA Neurology8. The patients were stratified according to clinical characteristics predictive of atrial fibrillation including left atrial size and frequency of premature atrial contractions. Nine percent of the total trial population had a left atrial diameter size greater than 4.6cms. Among this prespecified group, rivaroxaban was associated with a 1.7%/year rate of recurrent ischemic stroke as compared to 6.5%/year with aspirin. This is a statistically significant difference in favor of rivaroxaban- hazard ratio =0.26, P=0.02. This result indicates that rivaroxaban may be beneficial in patients with ESUS who are found to have at least moderate enlargement of the left atrium as these are the patients most likely to have underlying occult atrial fibrillation.

While these results are promising, the findings need to be confirmed with a randomized clinical trial. This is the premise of the ongoing ARCADIA trial9 which will enroll patients with a recent ESUS event and evidence of atrial cardiopathy defined by specific ECG changes, serum biomarkers and left atrial dilatation. The patients will be randomized to receive apixaban 5mg twice daily or aspirin 81mg daily. The results of this trial will hopefully guide treatment decisions for this patient group in the future. In the meantime, based on the current evidence, a broad utilization of anticoagulants cannot be recommended for prevention of ESUS. Physicians should strive to monitor these patients with longer term cardiac rhythm monitoring techniques such as implantable loop recorders.

 

References:

  1. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol. 1989 Apr;25(4):382-90
  2. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41
  3. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet        2014 Apr;13(4):429-38
  4. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014 Jun 26; 370(26):2467-77
  5. Cryptogenic Stroke and Underlying Atrial Fibrillation. N Engl J Med 2014; 370:2478-2486
  6. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med 2018; 378:2191-2201
  7. https://journals.sagepub.com/doi/full/10.1177/1747493018789543
  8. Recurrent Stroke with Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial. JAMA Neurol. 2019 Apr 8
  9. The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods. International Journal of Stroke 0(0) 1–8

 

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Aspirin: The Good, the Bad and the Ugly

Last week, I was talking to one of my patients about her ischemic stroke, which led her to be admitted to the hospital. I discussed that I would be prescribing a daily aspirin along with other medications to reduce her risk of recurrent stroke. She replied, “But doc! I just read on the news that aspirin is no longer recommended to prevent heart attack and stroke.” It took me a moment to realize that she was referring to the recently released guidelines for “primary prevention of cardiovascular disease.” I explained to her the rationale, benefits, risks and evidence supporting the use of aspirin for secondary stroke prophylaxis. She felt better after our detailed conversation and agreed to initiate the medication as recommended. Later that day, I read several potentially misleading headlines on major news media websites about this new guideline. The headline on CNN1 read, “Daily aspirin to prevent heart attacks no longer recommended for older adults,” while USA Today2 reported, “Don’t take an aspirin a day to prevent heart attacks and strokes.”

The guidelines issued by the ACC now recommend against routine use of aspirin for primary cardiovascular prophylaxis in adults older than 70 years. This new recommendation is based on the ASPREE trial, published in 20183. During this trial, healthy adults older than 70 years with no prior history of cardiovascular disease were randomized to receive 100 mg aspirin or placebo. The low dose aspirin lead to a significantly higher risk of major hemorrhage without a significant benefit in terms of cardiovascular event prevention. The guidelines recommend using low dose aspirin for primary prophylaxis of cardiovascular events only in adults aged 40-70 years who are at a higher risk of atherosclerotic cardiovascular disease. The guidelines no longer recommend using the 10 year estimated ASCVD risk threshold of 10%, but in fact propose a more tailored approach to primary cardiovascular prophylaxis.  Patients at a high risk of cardiovascular disease and whose risk factors are not optimized despite maximal medical therapy may be candidates for prophylactic aspirin at low doses. Physicians should have a careful discussion of the individual risks and benefit of aspirin before prescribing a daily aspirin regimen to their patients. Aspirin should not be prescribed for primary prophylaxis to patients with an increased risk of hemorrhage, such as a history of gastrointestinal bleeding or thrombocytopenia.

These guidelines are obviously for patients without a prior history of a cardiovascular events such as an MI or ischemic stroke. There is unambiguous data that supports the use of aspirin for secondary cardiovascular prophylaxis. My patient from last week belonged to this category and I started our aspirin discussion with her by explaining this clear distinction. She understood the rationale for aspirin in her case and how the new guidelines did not apply to her. The news headlines are sometimes sensationalized which can render them misleading for the reader. The two news articles did in fact report that the guidelines refer to use of aspirin in healthy older adults with no history of heart disease or stroke. In today’s world of fast paced digital information, there is a tendency to just read the headlines and move on to the next thing. This can be very problematic if patients on aspirin for secondary prophylaxis stop taking their medication after reading these news headlines.

As healthcare professionals, it is our responsibility to tackle this kind of misinformation which can lead to potentially bad outcomes for our patients. One of the ways to do that is to enhance our presence on social media platforms which are increasingly becoming the major source of news and information for the public. The AHA Early Career Blogging Program is one such avenue which can help young healthcare professionals strengthen their digital and social media footprint. This also helps facilitate collaborative projects and ideas among healthcare professionals and can lead to improved patient outcomes, which is the ultimate goal in all our endeavors.

 

References:

  1. https://www.cnn.com/2019/03/17/health/aspirin-heart-disease-guidelines/index.html
  2. https://www.usatoday.com/story/news/health/2019/03/18/aspirin-prevent-heart-attacks-strokes-doctors/3199831002/
  3. N Engl J Med 2018; 379:1509-1518 DOI: 10.1056/NEJMoa1805819

 

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Andexanet Alpha: Novel Reversal Agent for Factor Xa Inhibitors

Over the last decade, several direct oral anticoagulants have become available for thromboembolic prophylaxis, as an alternative to the Vitamin K antagonist warfarin. These agents are either direct thrombin inhibitors (dabigatran) or Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). In my clinical practice, I frequently prescribe these medications for stroke prophylaxis from atrial fibrillation. During these discussions with patients, I provide information from clinical trials comparing warfarin and the DOACs. These medications have shown similar stroke prophylaxis efficacy and safety in terms of hemorrhage risk when compared to warfarin. One of the concerns for patients and clinicians has been a lack of a reversal agent for the DOACs. There is some evidence to suggest that patients have better outcomes in case of hemorrhagic events while on DOACs as compared to warfarin1.

Prothrombin complex concentrate along with Vitamin K is used to treat warfarin associated major bleeding. Idaruzicumab was approved by the FDA in 2015 for reversal of dabigatran related major hemorrhages. Still acute life threatening hemorrhage while on Factor Xa inhibitors remains difficult to treat due to a lack of a specific reversal agent.

Final results from the ANNEXA-4 study were presented at the International Stroke Conference 2019 held at Honolulu earlier this month. The results were simultaneously published in the NEJM2. This trial investigated Andexanet alfa, a modified recombinant inactive form of human factor Xa. This binds to and sequesters factor Xa inhibitor molecules. This leads to rapid lowering of factor Xa inhibitor activity. ANNEXA-4 investigators  enrolled 352 adult patients who presented due to acute major bleeding in the setting of using a factor Xa inhibitor within the last 18 hours. Patients were eligible if they had an acute major bleeding in a critical organ, such as intracranial or retroperitoneal hemorrhage, bleeding associated with significant hemodynamic compromise, or significant drop in the hemoglobin level. 64% of the patients enrolled had an intracranial hemorrhage as their qualifying event. Patients with severe intracranial hemorrhage (GCS<7 or hematoma volume>60 ml) were excluded from the trial. The drug was infused as an initial bolus dose followed by a 2 hour infusion. Blood levels of Factor Xa inhibitor and anti-Factor Xa activity was measured before, during and after the infusion. Patients with intracranial hemorrhage received a follow up brain CT or MRI at 1 hour and 12 hours after the infusion.

There was a 92% reduction in the median values of anti-Factor Xa activity after administration of the bolus dose in patients who were on rivaroxaban or apixaban. At 12 hours after the infusion, 82% patients were noted to have an excellent or good hemostatic efficacy as determined by  pre-specified criteria. This is comparable to the 72% rate noted with prothrombin complex concentrate treatment given for reversal of warfarin related major bleeding. Thrombotic events occurred in 10% of patients within 30 days after the infusion, with almost half of these events being ischemic stroke. Interestingly, this study did not show a direct correlation between anti-Factor Xa activity reduction and clinical response. Among patients with intracranial hemorrhage, there was a weak relationship that was observed between hemostatic efficacy and anti-Factor Xa activity reduction. Therefore the investigators do not recommend using the anti-Factor Xa activity level as a predictor of clinical response. This study was limited due to its non randomized design. A randomized clinical trial is currently being initiated by the study sponsors to overcome this limitation3.

The FDA approved andexanet alpha in May 2018 for reversal of anticoagulation in case of severe life threatening bleeding related to apixaban or rivaroxaban. Intracranial hemorrhage is one of the most feared complications of long term anticoagulation and now we have available, effective and safe reversal agents for all the prescribed oral anticoagulants. This provides a significant benefit and reassurance for patients who are taking these medications for thromboembolic prophylaxis.

 

References:

  1. Compared to warfarin, direct oral anticoagulants are associated with lower mortality in patients with blunt traumatic intracranial hemorrhage: A TQIP study. J Trauma Acute Care Surg. 2016 Nov;81(5):843-848.
  2. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. February 7, 2019 DOI: 10.1056/NEJMoa1814051
  3. ClinicalTrials.gov number (NCT03661528)

 

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News from the International Stroke Conference: Minimally Invasive Surgery for ICH

Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and is associated with a high early mortality and poor long term functional outcomes. It is the only subtype of stroke which still does not have a proven and effective treatment available. Clinical trials investigating craniotomy and surgical evacuation of the hematoma have not shown improvement in outcomes1,2. Current in-hospital treatment of ICH has mainly involved medical stabilization and management of complications. More recently, there has been an increased interest in minimally invasive surgical methods for hematoma removal as a treatment strategy for intracerebral hemorrhage3.

Results of the recently concluded MISTIE III trial were presented at the International Stroke Conference in Honolulu earlier this week. This was an open label phase 3 trial which evaluated if minimally invasive catheter evacuation followed by thrombolysis can improve functional outcomes in ICH. The trial enrolled 499 adult patients with spontaneous/non traumatic supratentorial intracerebral hemorrhage measuring at least 30 ml. The patients were randomized 1:1 into the MISTIE and standard medical care groups.  Patients with a vascular etiology, such as an AVM or with an infratentorial hemorrhage were excluded from the study. The MISTIE treatment involved image guided catheter evacuation of the hemorrhage utilizing local thrombolysis with 1 mg alteplase doses given every 8 hours, up to a total of 9 doses.

Primary outcome was defined as a good functional outcome measured by modified Rankin Scale score of 0-3 at 1 year. 45% patients in the MISTIE group achieved the target primary outcome as compared to 41% in the medical care group. The 30 day mortality rates were 9% in the MISTIE group and 15% in the standard medical group. These results were not statistically significant to indicate a benefit of the minimally invasive surgical treatment. There was no significant difference in the rates of symptomatic bleeding and brain bacterial infections between the two treatment arms. Removal of the hematoma volume was associated with a significant increase in the probability of good outcomes. Patients who achieved final hematoma volume of less than 15 ml were more likely to have a good functional outcome in the MISTIE group:  53.4% vs. 41.9%, with p =0.03.

Even though the results were neutral without a signal towards overall benefit, this study does show that the minimally invasive surgery can be safely performed without an increase in the rates of death or other serious adverse outcomes. This is a promising result and should encourage further studies evaluating minimally invasive surgical treatments for ICH. Three ongoing trials are evaluating minimally invasive surgical treatments for ICH: ENRICH, INVEST and MIND (www.clinicaltrials.gov). With improved procedural protocols in the future, lowered hematoma volumes could be obtained more consistently, which would lead to better functional outcomes for this devastating neurological condition.

References:

  1. Mendelow AD Gregson BA Fernandes HM et al.Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365: 387-397
  2. Mendelow AD Gregson BA Rowan EN Murray GD Gholkar A Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013; 382: 397-408
  3. Hanley DF Lane K McBee N et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017; 389: 603-611
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Tenecteplase: Is It Ready for Primetime?

In 1996, intravenous alteplase was approved by the FDA for treatment of acute ischemic stroke within 3 hours of time of onset of symptoms. Since then it remains the only drug approved for treatment of acute ischemic stroke. Subsequent clinical trial showed benefit of alteplase unto 4.5 hours from onset of symptoms.

Over the past few years, several trials have studied medications including anticoagulants and thrombolytics, but have not shown positive results. Tenecteplase is a bio-engineered form of alteplase, and is approved in the U.S. for acute myocardial infarction. In 2017, results of the NOR-TEST trial were published, which compared the efficacy and safety of tenecteplase and alteplase in an open label, randomized design1. 1100 patients were randomized 1:1 to receive either alteplase 0.9 mg/kg (max dose 90 mg) or tenecteplase 0.4 mg/kg (max dose 40 mg).  Most patients enrolled in this study had a mild stroke with median NIH stroke scale of 4. The primary outcome measure of 3 months modified rankin score 0-1 was achieved in 64% of the tenecteplase group and 63% of the alteplase group. The mortality rates and serious adverse event rates were also similar in the two treatment arms. In conclusion, this study showed that tenecteplase had similar safety and efficacy as compared to alteplase when administered to acute ischemic stroke patients within 4.5 hours of symptoms onset.

A subsequent subset analysis of patients presenting within 3 to 4.5 hours time window also had similar results in the two treatment groups, with rates of good functional outcomes and adverse events including mortality2.

In the last few years, several clinical trials have established efficacy and safety of mechanical thrombectomy for treatment of ischemic stroke caused by acute occlusion of an intracranial internal carotid artery or middle cerebral artery. The American Heart Association/Stroke Association guidelines recommend treatment with intravenous alteplase in eligible patients ,prior to mechanical thrombectomy. The EXTEND-IA TNK trial3 studied the efficacy of tenecteplase 0.25 mg/kg (max dose 25 mg) compared to alteplase 0.9 mg/kg (max dose 90 mg) in patients who subsequently underwent mechanical thrombectomy fo an intracranial large vessel occlusion. The thrombolytic drugs were administered within 4.5 hours from symptom onset. The trial was designed as a non inferiority study but showed tenecteplase to be superior than alteplase. The primary outcome of greater than 50% reperfusion of the occluded artery at the time of initial angiogram was achieved in 10% of the alteplase group and 22% in the tenecteplase group (P= 0.03 for superiority and P=0.02 for non inferiority). Moreover, tenecteplase resulted in better functional outcomes measured by median modified rankin scores at 90 days ( 2 vs 3, P=0.04). Both the treatment groups had similar rates of symptomatic intracerebral hemorrhage.

Tenecteplase has better fibrin specificity and a longer half life than alteplase. Tenecteplase can be administered as a bolus over a few seconds while alteplase requires a one hour infusion. A significant proportion of large vessel occlusion stroke patients receive intravenous thrombolysis at the initial hospital and then get transferred to a larger stroke center for mechanical thrombectomy; this is referred to as the drip and ship approach. The one hour infusion is usually initiated at the first emergency department and continued en route to the thrombectomy center. This approach can pose logistical challenges and cause treatment delays, which can be overcome if a thrombolytic can be rapidly administered as a bolus prior to patient getting transferred.

These results have now shown that tenecteplase is a promising alternative to the current standard of care thrombolysis with alteplase when treating acute ischemic stroke. This may be especially favorable for the patients who also require mechanical thrombectomy of an intracranial large vessel occlusion.

Further research is needed to establish the efficacy and obtain regulatory approval for tenecteplase in treatment of acute ischemic stroke. ATTEST-2 is an ongoing trial studying the efficacy of tenecteplase in ischemic stroke not caused by a large vessel occlusion. EXTEND-IA TNK-2 is going to compare two doses of the tenecteplase (0.25 mg/kg and 0.40 mg/kg) for safety and efficacy.  It is exciting to think that we may be getting close to the first new drug approved for treatment of acute ischemic stroke in more than 20 years.

References

  1. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017 Oct;16(10):781-788.
  2. Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Stroke. 2019;0
  3. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582

 

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Antithrombotic Medications: Is More Better?

During Scientific Sessions 2018, I was able to remotely attend several great and informative lectures pertaining to the management of cardiovascular diseases. I was especially interested in the sessions related to antithrombotic therapy as this directly applies to my daily practice of Vascular Neurology. One of those sessions focused on management of tricky situations in post PCI patients. Dr. Roxana Mehran discussed the management of patients with atrial fibrillation and a recent PCI.

Antiplatelet medications are used for secondary prophylaxis in patients with coronary artery disease and ischemic stroke. Patients are routinely prescribed dual antiplatelet therapy (DAPT), usually a combination of aspirin with a P2Y12 inhibitor such as clopidogrel, ticagrelor or prasugrel. This is usually continued for six to 12 months after a PCI.

Results from the recently published POINT (1) trial showed reduced risk of recurrent ischemic stroke in the  short term but an increased risk of hemorrhage with long term use of DAPT for patients with a recent TIA or minor stroke. Data from the SPS-3 (2) trial showed increased risk of hemorrhage with no clear benefit of using DAPT when compared to monotherapy in secondary stroke prevention for patients with a history of lacunar stroke. Therefore, patients who have experienced a recent transient ischemic attack or minor stroke are prescribed a short course of DAPT for 21-30 days.

DAPT has been shown to be inferior to warfarin for embolic stroke prophylaxis, with similar bleeding risk in atrial fibrillation(3). Therefore oral anticoagulants are the treatment of choice for atrial fibrillation. The AHA/ASA guidelines recommend against using DAPT in place of warfarin for atrial fibrillation in high bleeding risk patients.

About 5-10% of patients who undergo PCI are also taking an oral anticoagulant for atrial fibrillation. This creates a tricky situation where they need to be on triple therapy with DAPT and an oral anticoagulant. The triple therapy regimen has been associated with a significantly elevated risk of hemorrhage. WOEST (4) study data showed that using the combination of clopidogrel and an oral anticoagulant after PCI can reduce this risk as compared to the triple therapy regimen. The triple therapy arm 44.4% patients experienced a bleeding episode as compared to 19.4% in the double therapy arm (p<0.001). Moreover there was a higher rate of recurrent bleeding in the triple therapy group at 12% vs. 2.2% in the double therapy cohort. Most importantly, the double therapy did not cause an increase in the incidence of stent thrombosis or recurrent myocardial infarction. These data are encouraging and there are ongoing trials comparing various combination regimens of direct anticoagulants with antiplatelets in this difficult clinical scenario. These much awaited trials will hopefully provide some clarity regarding the optimal combination and duration of treatment. For now, we do have some evidence supporting the use of these triple therapy regimens for the shortest durations possible and periodically assessing the indications for continuing these combination regimens for our patients. When it comes to antithrombotic medications, more may not always be better.

 

References

  1. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379:215-225
  2. Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke. N Engl J Med 2012; 367:817-825
  3. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12
  4. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15

 

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New Cholesterol Guidelines From A Neurologist’s Perspective

The American Heart Association’s annual premier conference “Scientific Sessions 2018” concluded on Monday. This meeting showcases the latest advancements and discoveries in the field of cardiovascular medicine and is attended by clinicians and researchers from across the world.

Being a vascular neurologist, I have attended the International Stroke Conference organized by the AHA several times, however, this was my first time attending Scientific Sessions. I was able to attend the conference via Live Streaming while sitting in my office in Burlington, Massachusetts.

There are a lot of overlaps between cerebrovascular and cardiovascular disease and I was particularly interested in attending the sessions pertaining to stroke prevention and brain health. One of the most anticipated presentations was the release and discussion of the new AHA/ACC Cholesterol Clinical Practice Guidelines.

Some key takeaways from the updated guidelines:

  • The guidelines continue to underscore the role of lifestyle and dietary habits in addition to lipid lowering medication use to treat cholesterol disorders. There is emphasis on the concept of shared decision making with the patient which should include discussion of their individual risk and the treatment options to reduce that risk.
  • Addition of Ezitimibe and subsequently PCSK-9 inhibitors is now recommended in patients who cannot achieve target LDL levels despite maximum tolerated statin doses. There is some concern about the cost effectiveness of PCSK-9 inhibitors, but these medications are expected to become cheaper in the future.
  • Risk enhancing factors are introduced as part of a personalized approach to risk assessment prior to initiating statin therapy. These include persistent elevation of LDL>160 mg/dL, history of pre-eclampsia, family history of premature atherosclerotic cardiovascular disease, history of chronic kidney disease and chronic inflammatory disease, among others.
  • There is a recommendation for expanding use of calcium score as part of the risk assessment, especially in patients where risk benefit analysis is uncertain.

 

In addition to the guidelines for medications and lifestyle changes to treat cholesterol disorders, I especially enjoyed Dr. Laurence Sperling’s talk about the safety of statins.

Patients should be prescribed statins again at a lower dose or modified drug regimen if the reason for discontinuation was mild side effect symptoms. Although rare, but some patients do develop severe myopathy with statin use. These patients should be prescribed alternate non-statin therapies to achieve the target cholesterol levels. There has not been any proven benefit of Co Q10 to prevent or treat statin associated muscle symptoms. Despite the increased risk of diabetes mellitus with statins, it is recommended to continue the drug in patients who may be at risk or develop new onset DM. These patients should be counseled about the net clinical benefit of these drugs for long term cardiovascular event prevention. It appears reasonable to initiate statin therapy in the presence of an appropriate indication despite a history of stable liver disease. In patients without hepatic disorders, there is no clinical benefit of routine creatine kinase and liver enzyme measurements.

Very often patients have questions and concerns about initiating and continuing their statin medication. I believe that these data and recommendations further reinforce my personal practice to encourage patients to continue their statin medication as the risk benefit ratio remains favorable despite mild side effects.