stroke

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Aspirin: The Good, the Bad and the Ugly

Siddharth Sehgal, MD

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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Success Does Not Always Leave A ‘Footprint’

Abhishek Sharma, MD

Stroke is one of the leading causes of mortality and morbidity in the United States (US). Approximately one‐third of all ischemic strokes are considered cryptogenic, i.e not attributed to large‐vessel atherosclerosis, small‐artery disease, or embolism despite extensive vascular, serological, and cardiac evaluation. Until recently, the relationship between patent foramen ovale (PFO) and cryptogenic stroke was highly debated. Prior to 2006, use of transcatheter based PFO closure procedures were only permitted under Food and Drug Administration (FDA) Humanitarian Device Exemption for recurrent cryptogenic stroke from a PFO after failed conventional medical therapy1. However, the number of eligible patients exceeded the regulatory mandated annual limit of 4,000 patients in 2006. Thus, the Humanitarian Device Exemption process was voluntarily withdrawn1.

In the past two decades, several randomized clinical trials using the Amplatzer PFO Occluder, the Starflex Septal Occluder (NMT Medical Inc, Boston, MA), and the Gore Cardioform Septal Occluder were conducted. Based on long term follow up results of the RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment] and REDUCE [GORE® Septal Occluder Device for PFO Closure in Stroke Patients] trials, US FDA approved the Amplatzer PFO Occluder in 2016 and the Gore Cardioform Septal Occluder in 20181,2.  FDA approval for these devices for PFO closure in the United States is “to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke2.”

Despite proven efficacy, the use of device based PFO closure techniques have potential risks of several early and late complications, including infection, thrombosis, device dislodgement, atrial wall erosion, perforation, fracture, migration-embolization, allergic reaction to nickel used in PFO occluder device, and induction of arrhythmias3,4. Further, there is need of post procedure antiplatelet therapy after implantation of these devices. These concerns lead to need for a ‘deviceless’ transcatheter system to close PFO. Ruiz et al have performed first-in-man transcatheter suture closure of a PFO in an 18-year-old female with chronic migraine with aura in 2008 without leaving ‘footprint’5.  Results of this novel approach were exciting; however, safety and efficacy of ‘deviceless’ transcatheter techniques on large scale was not established until early results of the NobleStitch EL Italian Registry were reported few months ago6. In this prospective registry, investigators successfully used suture based PFO closure system in 186 (out of 192) patients across 12 sites in Italy with no device related complication on 206±130 days follow-up6. FDA approves the NobleStitch™ EL for Vascular and Cardiovascular suturing in the US (interestingly the technique is not specifically labeled for treating PFOs).

Due to projected increase in numbers of left sided transcatheter interventions (e.g. left atrial appendage closure, arrhythmia ablation and mitral valve interventions), the deviceless technique could be a very attractive option in selected patient population as presence of interatrial septal prosthesis make trans-septal puncture more challenging. Though this technology has huge potential, we should still wait for long term data on safety and efficacy of this no foot print PFO closure system before advocating and supporting its widespread use.

 

References:

  1. Writing Group Members , American Heart Association Statistics Committee; Stroke Statistics Subcommittee . Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016; 133:e38–e360
  2. .https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm527096.htm
  3. Luermans JG, Post MC, Yilmaz A. Late device thrombosis after atrial septal defect closure. Eur Heart J. 2010;31:142
  4. Merkler AE, Gialdini G, Yaghi S, Okin PM, Iadecola C, Navi BB, Kamel H. Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale. Stroke. 2017;48:3073-7
  5. Ruiz CE, Kipshidze N, Chiam PT, et al. Feasibility of patent foramen ovale closure with no-device left behind: first-in-man percutaneous suture closure. Catheter Cardiovasc Interv. 2008 Jun 1;71(7):921-6.
  6. Gaspardone A, De Marco F, Sgueglia GA, et al. Novel percutaneous suture-mediated patent foramen ovale closure technique: early results of the NobleStitch EL Italian Registry. EuroIntervention. 2018 Jun 8;14(3):e272-e279.

 
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Eye and the Brain

Trupti Shetty

An eye oftentimes feels like the most underappreciated systems in the field of vascular biology. An eye is a highly vascular organ than it gets credit for, and here’s why – ranging from high blood pressure or diabetes to early signs of stroke, an eye exam can, in fact, tell a physician a lot about one’s health. In a series of blog posts, I decided to highlight these key connections between the eye and the human body. This article will focus on the current knowledge linking eye and the brain.

 

One of the common cerebral diseases caused by blood vessels is stroke. Stroke, typically caused by a blood clot, can either be a chronic or acute ischemic complication. This eventually leads to loss of function in the brain and hemorrhaging (bleeding) in the related part of the brain, retina, or spinal cord. Many risk factors shared by cardiovascular diseases converge with risk factors for stroke. For example – hypertension, diabetes, and alcohol consumption can all increase incidence of stroke related problems.

In my previous blog, I explained how retinal microvessels can be a window to the vessels in the body. Dimensions like caliber (diameter) of retinal vessels can be measured noninvasively, and how they strongly correlated with cardiovascular risks. This article will focus on how, this is also resonant in case of vessels of the brain (cerebrovascular). Physiologically and anatomically, vessels in the retina and the brain share many similarities. Most commonly known would be the blood-brain barrier and the retinal-blood barrier, maintained by tight junctions that are essentially bouncers found outside a club. Even with advanced imaging technologies, capturing these neurovessels can be very challenging. Serendipitously, retinal photographs can thus be used to provide information like signs of stroke or predictors of stroke or dementia, as detailed in this article. Retinal fundus photograph of a patient (as seen in picture) shows embolism or blockage caused by cholesterol-like deposits, and are strongly associated with increased risk of stroke-related death as detailed in a study.

(source: https://doi.org/10.1161/STROKEAHA.107.496091)

One study, specifically the measurements of retinal vessels and compared its association with acute ischemic stroke in a population study. Even the subtlest changes in the retinal vessels of stroke patients were reported, which stood out on comparison with healthy patients. Interestingly, changes in dimensions of retinal vessels were also found in patients with dysfunction in cognitive behavior, suggesting similar tests can be used to diagnosing diseases like dementia and Alzheimer’s (more on this in future posts). Another common indicator between stroke and the retina was found in the retinal nerve fiber layer. Although this is slightly different than comparing the blood vessels, a research group found strong correlation between defects in the nerve fiber layer and acute stroke.

In conclusion, many research groups are now considering using tools to assess retinal vessels for diagnosis of cerebrovascular diseases. More studies in this area, can then suggest a very powerful and noninvasive diagnostic method, which could help both the patient population and the clinicians.

 

 
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Going to Honolulu, Hawaii Bae-Bae!!!

Anberitha Matthews, PhD

The International Stroke Conference 2019 (ISC19) is held in conjunction with the International Society of Cerebral Blood Flow and Metabolism (ISCBFM) this year. This session promises a unique learning opportunity. The meeting expectations is for participants to be exposed to the most recent advances in basic stroke and how it translates into clinical research. Additionally, the program coordinators expect attendees to take away tools they can use in diagnosis, treatment, prevention, management, and rehabilitation of cerebrovascular disease. With the tools discussed during this conference, scientist/clinicians will have a new repertoire of skills to increase their ability to interpret the ever changing spectrum of stroke and the mechanism of stroke recovery, as well as the impact on cognitive impairment.

The dual effort of @AHAMeetings #ISC19 and #ISCBFM allows for this program to boast three separate pre-conferences symposia, including the State-of-the-Science Stroke Nursing Symposium, the ISC Pre-Conference Symposium I: Stroke in the Real World (focusing on rare causes of stroke), and the ISC Pre-Conference Symposium II: Stroke in the Lab World: Cutting-Edge Topics in Experimental Stroke Research. The expected attendance of over 4,500 professionals, exhibitors, and service from around the world makes for a networking friendly environment. There will be over 1,500 symposia including: a) debates, b) oral scientific abstract presentations, c) provocative poster sessions that include professor-moderated abstracts, and d) state-of-the-science technologies that include simulations. There are going to be over 21 categories covered related to stroke topics as well as clinical topics centered on risk, emergency care, neuroimaging, diagnosis or etiology and more! Basic science categories will focus on vascular biology, experimental mechanisms and models. If those are not enough, there will be specialized ones focused on pediatric stroke, intracerebral hemorrhage, nursing, preventive strategies, vascular cognitive impairment, aneurysms, subarachnoid hemorrhage, neurocritical care, vascular malformations, and ongoing clinical trials. Further, Miguel Perez-Pinzon, Chair of the ISC19 program committee, promises a chance to experience the island of Oahu for education and networking with thousands of cerebrovascular experts from around the globe. He described Oahu as “truly one island – tropical playground and urban fantasy.” Partake in one of the many outdoor activities, explore the rich Hawaiian history, or just enjoy one of the exquisite beaches.

I know it’s a lot of science and clinical data for one conference, and there is no way for any one person to attend every session. There will be a lot of vascular enthusiasts like me onsite, tweeting and blogging all the goings-ons. I will look forward to communicating with you on Twitter during this conference in Hawaii, but don’t forget to download the ISC19 Mobile Meeting Guide app, or visit strokeconference.org and the online program planner. Follow me on Twitter @AnberithaT for conference highlights and live tweeting. See you in Hawaii!!!

 

Save the Date for ISC 2020, February 19 – 21, hosted in exciting Los Angeles, California!

 
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Tenecteplase: Is It Ready for Primetime?

Siddharth Sehgal, MD

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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Can We Use Observational Data To Improve Clinical Management of Stroke Patients?

Reem Waziry, MD, MPH, PhD

Randomized clinical trials (RCTs) contributed the most to our knowledge to date in management of stroke patients. Despite the strengths of RCTs, they can be very costly and sometimes not feasible.

In this year AHA Scientific Sessions, Jonathan P. Piccini, MD highlighted areas where observational data have been informative to address difficult clinical questions that couldn’t be addressed by RCTs alone. Key areas include: the role of bleeding scores in guiding stroke prevention treatment decisions1, withholding oral anticoagulation in patients with significant contraindications2, the role of oral anticoagulants in improving prognosis of patients with end-stage renal disease3, and the role of concomitant aspirin in improving outcomes in patients on oral anticoagulant therapy4. Thus, there are many examples where observational data provided key insights in management of stroke patients (from a clinical epidemiology perspective) on risk factors, disease progression, treatment utilization and its patterns, comparative safety and effectiveness. Most importantly, those investigations were key to highlight knowledge gaps and generate hypotheses to guide or build on existing RCTs data.

Moving forward, to further advance the translation of observational data to clinical practice, there is a need for: 1) collaborative efforts to merge diverse observational data sets, and 2) more focused investigations to refine our analytical methods with specific applications in the stroke population.

 

REFERENCES

  1. Pisters, R., Lane, D. A., Nieuwlaat, R., De Vos, C. B., Crijns, H. J., & Lip, G. Y. (2010). A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.Chest, 138(5), 1093-1100.
  2. Shah, M., Avgil Tsadok, M., Jackevicius, C. A., Essebag, V., Eisenberg, M. J., Rahme, E., … & Pilote, L. (2014). Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis.Circulation, 129(11), 1196-1203.
  3. Pokorney, S. D., Simon, D. N., Thomas, L., Gersh, B. J., Hylek, E. M., Piccini, J. P., & Peterson, E. D. (2016). Stability of international normalized ratios in patients taking long-term warfarin therapy.Jama, 316(6), 661-663.
  4. Hsu, J. C., Maddox, T. M., Kennedy, K. F., Katz, D. F., Marzec, L. N., Lubitz, S. A., … & Marcus, G. M. (2016). Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: insights from the NCDR PINNACLE registry.JAMA cardiology, 1(1), 55-62.

 
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Management of Stroke Patients: A One Man Show or A Tag-Team?

Reem Waziry, MD, MPH, PhD

Atrial fibrillation (AF) increases risk of stroke up to 5 folds, resulting in considerable physical, cognitive impairment and high mortality1. Thus, AF related strokes are very expensive to treat compared to non-AF strokes2. Oral anticoagulation is a well-established therapy in the majority of stroke cases3. Warfarin reduces the risk of stroke by 64% and mortality by 30% compared to placebo3.

Recent data from the pinnacle registry presented by ‘Roopinder Sandhu, Edmonton, AB, Canada’ at the Scientific Sessions 2018, highlighted three key challenges in anti-coagulants management in stroke patients4. Data from a national outpatient registry reported over 700,000 patients had a diagnosis of atrial fibrillation5. Although oral anticoagulation use increased over time, around 40% of patients who are eligible for anti-coagulation never got started on therapy5. The second gap is sub-therapeutic dosing. Recent data from the orbit registry evaluated over 5700 patients who were recently started on a new drug and reported that one in eight patients were either underdosed or overdosed6. Further, there was a higher rate of adverse events in patients who had dosing that was sub therapeutic. The third gap is non-adherence. Data from administrative claims based on a large U.S. commercial insurance database, calculated adherence based on the fill date and the days of supply on the pharmacy claims over a median of 1.1 years7. Less than half of patients who were started on a drug therapy reached the threshold of proportion days covered of 80% or higher. This proportion was less for patients who were on Warfarin.

Given the public health consequences of untreated AF, it is necessary to evaluate different strategies to deliver stroke prevention therapy. Data from 30 randomized clinical trials evaluating the impact of pharmacists, versus standard care, showed superior results in the pharmacist care group in reducing systolic blood pressure (by 8 mm HG), diastolic blood pressure (by 4 mm HG) and total cholesterol (by 17 milligrams DL) and LDL (by 13 mg DL)10. This was done through educational intervention and identification of drug related problems followed by early feedback to the treating physician.

Roopinder added a few possible explanations to what could be driving such impact in the Canadian setting. Typically, a general practitioner would be dealing with patients with a higher evidence of chronic diseases. Further, patient demands often exceed the available physician capacity.

While these results collectively suggest that pharmacist led strategies may be a promising way forward because of their accessibility, drug expertise and their ability to build a trusted relationship. A few key things should be considered. First, that anticoagulation remains to be a complicated problem when it comes to individual patients, with many factors playing a role in the decision process including; medical history (as prior bleeding) and patient preferences. Second, while these interventions seem beneficial in the short-term it may lead to the same shortcomings in the long-term with the increase in demand on the pharmacists as the main provider.

Finally, a key question remains, would a collaborative approach between physicians and pharmacists yield better outcomes through reducing the burden on both providers and simultaneously increasing the time allocated to stroke patients on a case-by-case basis?

 

REFERENCES

  1. Developed with the special contribution of the European Heart Rhythm Association (EHRA), Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS), Authors/Task Force Members, Camm, A. J., Kirchhof, P., Lip, G. Y., … & Al-Attar, N. (2010). Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European heart journal, 31(19), 2369-2429.
  2. Stewart, S., Murphy, N., Walker, A., McGuire, A., & McMurray, J. J. V. (2004). Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart, 90(3), 286-292.
  3. Ruff, C. T., Giugliano, R. P., Braunwald, E., Hoffman, E. B., Deenadayalu, N., Ezekowitz, M. D., … & Yamashita, T. (2014). Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet, 383(9921), 955-962.
  4. Sandhu, R. K., Guirguis, L. M., Bungard, T. J., Youngson, E., Dolovich, L., Brehaut, J. C., … & McAlister, F. A. (2018). Evaluating the potential for pharmacists to prescribe oral anticoagulants for atrial fibrillation. Canadian Pharmacists Journal/Revue des Pharmaciens du Canada, 151(1), 51-61.
  5. Marzec, L. N., Wang, J., Shah, N. D., Chan, P. S., Ting, H. H., Gosch, K. L., … & Maddox, T. M. (2017). Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. Journal of the American College of Cardiology, 69(20), 2475-2484.
  6. Steinberg, B. A., Peterson, E. D., Kim, S., Thomas, L., Gersh, B. J., Fonarow, G. C., … & Piccini, J. P. (2015). Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation, 131(5), 488-494.
  7. Yao, X., Abraham, N. S., Alexander, G. C., Crown, W., Montori, V. M., Sangaralingham, L. R., … & Noseworthy, P. A. (2016). Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. Journal of the American Heart Association, 5(2), e003074.
  8. Santschi, V., Chiolero, A., Burnand, B., Colosimo, A. L., & Paradis, G. (2011). Impact of pharmacist care in the management of cardiovascular disease risk factors: a systematic review and meta-analysis of randomized trials. Archives of internal medicine, 171(16), 1441-1453.

 
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WATCHMAN: An Alternative to Warfarin for the High Risk Patient

Christian Perzanowski, MD

“Wisdom consists of the anticipation of consequences”
Norman Cousins

I recently saw Mr. John Doe for atrial fibrillation (AF). Well into his eighties, he enjoys a good quality of life. This elderly gentleman is mostly unaware of his paroxysms of AF. However, he had also suffered a stroke in the past, and as such was managed with warfarin. He was lucky. Recently, he experienced a gastrointestinal hemorrhage, requiring temporary reversal of his anticoagulant in addition to receiving a few pints of blood. There were no apparent clinical triggers for this event. Mr. Doe is not a fictional person but is a typical example of what is a common clinical dilemma: how best to protect against stroke in a patient who is at high risk, yet becomes intolerant to warfarin.

Previously, these patients were commonly switched to aspirin alone as a poor alternative to anticoagulation. Most clinicians would feel apprehensive of taking a gamble switching to novel oral anticoagulants which do not have available reversal agents (at the time this blog was written).

So, what then?

Enter the “Watchman.”

The majority of thromboembolic strokes in patients with AF originate in the left atrial appendage (LAA). The function of this structure is to assist with atrial transport, however during AF, atrial blood flow becomes impaired and stasis can occur in the LAA leading to thrombus formation at this location. Fragmentation and embolization of thrombi can lead to stroke, which is commonly disabling. The presence of comorbid factors such as diabetes, heart failure among other clinical variables can further increase this risk [1].

The last several years has witnessed the development and refinement of procedures referred to as left atrial appendage occlusion. Although there are several of the devices available worldwide, I will refer to the WATCHMAN system which is approved for use in the United States. In brief, the WATCHMAN device resembles a small umbrella (Figure 1). The FDA approved the device for the purpose of preventing embolic stroke with non-valvular AF. The available data that lead to its approval implies a non-inferiority to warfarin [2,3]

the WATCHMAN device resembles a small umbrella

Figure 1. (accessed from www.bostonscientific.com; www.modernhealthcare.com)

The method of device introduction is via a femorally placed venous sheath delivered transseptally (from right to left atrium). The destination of the device is the ostium of the LAA (Figure 2). The ultimate goal of the procedure is to totally exclude the LAA from the chamber, thus preventing flow into and from the LAA, in effect precluding thrombus formation. The procedure is performed with the guidance of transesophageal echocardiography, and typically under general anesthesia. The duration of the implant typically does not exceed an hour. Patients are continued on warfarin during the initial perioperative phase.

the destination of the device is the ostium of the LAA

Figure 2. (Accessed from www.bostonscientific.com; openaccessjournals.com)

Generally, after a forty-five-day period, transesophageal echocardiography is repeated to confirm the absence of peri-device leaks and verify device endothelialization. If the results are favorable, patients can often stop warfarin and switch to antiplatelet therapy. Presently, the available evidence compares WATCHMAN to warfarin, and comparisons to other anticoagulants is lacking.

It appears that enthusiasm for the WATCHMAN appears to be growing. For patients who require long-term warfarin use, but are at risk for hemorrhagic complications, this device appears to be a very good option. Cumulative experience will invariably lead to further improvements in design and greater safety [4,5].
 
References

  1. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950-62
  2. Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014;64:1-12
  3. https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=2 81&bc=ACAAAAAAAgAAAA%3d%3d&
  4. Reddy VY1, Doshi SK2, Kar S3, Gibson DN4, Price MJ4, Huber K5, Horton RP6, Buchbinder M7, Neuzil P8, Gordon NT9, Holmes DR Jr10; PREVAIL and PROTECT AF Investigators. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials.J Am Coll Cardiol. 2017;70:2964-2975
  5. Obeyesekere MN.Watchman Device: Left Atrial Appendage Closure For Stroke Prophylaxis In Atrial Fibrillation.J Atr Fibrillation. 2014; 7: 1099

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

Apollo Beach, FL (05/17, CP)
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A different kind of extended window for stroke treatment

Neal Parikh, MD

To fanfare at International Stroke Conference 2018, the results of the DEFUSE 31 extended window thrombectomy study were announced. The American Heart Association/American Stroke Association acute ischemic stroke guidelines were immediately updated to reflect the practice-changing findings. 

A few months later, Lee Schwamm and colleagues published their findings from MR WITNESS.2 In this study, patients with unwitnessed stroke onset between 4.5 and 24 hours underwent advanced magnetic resonance imaging to identify those individuals with radiographic evidence of hyperacute stroke. Based on prior work, it was known that evolution of imaging characteristic with respect to the fluid-attenuated inversion recovery (FLAIR) sequence correlates with time from onset. Patients who met imaging criteria based on the mismatch between FLAIR signal change and diffusion restriction were given tPA.

The researchers enrolled 80 individuals at multiple centers. Patients were treated at a median of 11 hours from their last known well. The rates of adverse events were very low and within the range of adverse event rates observed in prior stroke treatment trials. 

The standard stroke treatment paradigm allows patients to be treated within 4.5 hours of symptom onset. In general, patients treated beyond this window are at greater risk of brain hemorrhage and poor outcomes. The results of this Phase 2a study challenge the 4.5 hour time window. Like DEFUSE 3, this study uses advanced imaging to personalize acute stroke treatment. A frequent reason for patients to not receive tPA for stroke treatment has been that patients often present to hospitals too late. Expanding the time window for non-large vessel occlusion strokes, which are the vast majority of strokes but nonetheless disabling, has great public health implications. With the rest of the stroke community, I look forward to results of an efficacy trial.

References

  1. Albers GW, Marks MP, Kemp SK, Christensen S, Tsai JP, Santiago O, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM 2018; 378:708-718.
  2. Schwamm LH, Wu O, Song SS, Ford AL, Hsia AW, Muzikansky A, Betensky RA, et al. Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol 2018 Apr 24 [Epub ahead of print].

Neal Parikh Headshot

Neal S. Parikh, MD, earned his MD from Weill Cornell Medical College and completed residency training in neurology at the same institution. He is now an NIH T32 neuro-epidemiology and vascular neurology fellow at New York-Presbyterian Hospital/Columbia University Medical Center. He tweets @NealSParikhMD and contributes to Blogging Stroke as a blogger.
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Science of Strokes

Anberitha Matthews, PhD

types of strokesIt has been well accepted that atherosclerosis is the result of chronic inflammation. I have spent several years exploring the role endocannabinoids, lipid-based neurotransmitters that bind to receptors that are expressed throughout the peripheral and central nervous system, play in decreasing oxyradical derived inflammation. Under normal conditions, lipids are metabolized and excreted from the body. It is my belief we have an endogenous mechanism that maintains balance within the vascular system that protects our arteries from becoming damaged; however, in the event of an injury the immune system is activated leading to cardiovascular dysfunction.

Flow resistance, sheer stress, ischemic reperfusion, and oxidized low-density lipoproteins (oxLDL) can contribute to microvascular dysfunction particularly at non-linear area of a vessel. The pathology of atherosclerosis/stroke starts with the monocytes being recruited to an injured site causing the production of NADPH oxidase-derived reactive oxygen species (ROS). The monocytes undergo a phenotypic change into macrophages and uncontrollably engulf the oxLDL and subsequently lead to the development of lipid laden foam cells. Apoptosis of the foam cells occurs due to their inability to metabolize the modified reactive lipid peroxidation products. The extracellular matrix becomes remodeled resulting in the formation of a fibrous cap. It is this cap that causes the occlusion of a vessel causing a heart attack or stroke.

circulating moncyte, macrophage and foam cellAll strokes are not alike, they include ischemic, hemorrhagic, and transient ischemic attacks (TIA). Although older persons are thought to be the primary risk group for strokes, children and fetus can potentially be included in the risk population. The most common type is ischemic stroke caused by clots occluding the blood flow to the brain. The clots can be from congenital heart defects, sickle cell disease, and trauma that injures a large artery; however, they can also be a consequence of high cholesterol, oxLDL, and blood clots as well as exogenous and endogenous toxins. The foam cells in the artery can be either a stable plaque (solid fibrous extracellular tissue with small amounts of lipid) or vulnerable plaque (consist of macrophages and lipids in the artery wall that erosion prone). These “culprit” plaques are the cause of disruption in blood flow that leads to vascular events such as heart attacks and strokes. Hemorrhagic strokes are due to a rupture in the blood vessel that bleeds to the deep tissue of the brain; often caused by hypertension, but also aging vessels, arteriovenous malformations (cluster of deformed blood vessels), and aneurysms (a balloon of blood in the artery). Intracerebral hemorrhages are the most common type due to the prevalence of high blood pressure but can also be caused by exogenous toxins such as smoking, oral contraceptives with high estrogen, alcohol, and illegal drugs. TIAs often called mini-strokes, produce symptoms similar to those of stroke but without the lasting effects. They are thought to be warning signs to an ischemic stroke; the clots that cause them may be resolved without treatment, but without treatment they can lead to further strokes or death.

A recent report by Wang and colleagues demonstrated a linear correlation between oxLDL and the National Institutes of Health Stroke Scale (NIHSS). The results of their study indicated after adjusting for age, gender, ethnicity, and marriage, NIHSS score increased 1 μg/dL of oxLDL.  Preparedness is the best defense to preventing a stroke. The Hip-Hop Stroke randomized trial suggest that preparedness can potentially delay a major thrombolysis event. Visits to a medical professional to recognize the symptoms will play a major role in prevention. Since atherosclerosis and stroke are complex process that involve oxyradical stress, immune dysfunction, and vulnerable vessels and the NIHSS score is widely used in the clinical setting to evaluate LDLs in plasma, one can only delineate that being prepared by getting tested is the best way to validly and reliably be prepared to combat a stroke. If you find someone displaying stroke symptoms act FAST to give the best prognosis. Share with me your experience or experiences you have heard of to combat the detrimental effects of stroke.

Anberitha Matthews, PhD is a Postdoctoral Fellow at the University of Tennessee Health Science Center in Memphis TN. She is living a dream by researching vascular injury as it pertains to oxidative stress, volunteers with the Mississippi State University Alumni Association, serves as Chapter President and does consulting work with regard to scientific editing.