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

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 journal31(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. Heart90(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 Lancet383(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 Canada151(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 Cardiology69(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). Circulation131(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 Association5(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 medicine171(16), 1441-1453.

 

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WATCHMAN: An Alternative to Warfarin for the High Risk Patient

“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

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

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.

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Promising Advance In Stroke Thrombolysis Research: Tenecteplase

A recent New York Times article re-surfaced the ‘debate’ regarding alteplase (IV-tPA) for ischemic stroke.1 There are some who continue to argue that the data for IV-tPA are not convincing. In this context, and otherwise, it is worthwhile to discuss a recent study comparing tenecteplase versus alteplase among patients with large vessel occlusion.2

In this study, 202 patients presenting within the IV-tPA treatment window of 4.5 hours and with an ischemic stroke due to large vessel occlusion were randomized to receive IV-tPA versus IV-tenecteplase prior to proceeding with mechanical thrombectomy. The main outcomes relevant for this discussion are the primary outcome of substantial reperfusion (restoration of blood flow in the affected area) and the safety outcome of brain hemorrhage.

Whereas 10% of patients who had received IV-tPA achieved substantial reperfusion prior to undergoing mechanical thrombectomy, 22% achieved substantial reperfusion in the tenecteplase group. The number of brain hemorrhages was the same in both groups (5-6%).

If confirmed, this represents a tremendous advance in thrombolysis because many patients require lengthy transport to reach a center where thrombectomy can be performed. Achieving reperfusion without increased risk of hemorrhage, potentially in the field using stroke ambulances and telemedicine, could dramatically improve population-level care for this otherwise very disabling form of stroke.

Further, these data suggest support the stability of the 6% estimate of brain hemorrhage risk with IV-thrombolysis. The observation that the hemorrhage risk (5 vs 6%) was the same regardless of reperfusion rate (10 vs 22%) is intriguing – if the two are independent, is the risk of hemorrhage from thrombolysis from something other than reperfusion? Further, the results of this study will spur additional study and we will thus have contemporary, high-quality data regarding the efficacy and safety of thrombolysis.

References

  1. https://www.nytimes.com/2018/03/26/health/stroke-clot-buster
  2. Campbell, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. NEJM. 2018:378:1573-82.

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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Women’s Heart Disease – The Interdisciplinary Road Ahead

Every 80 seconds a woman dies from a heart attack or stroke. Once thought to be predominantly found in men, coronary heart disease remains the leading cause of morbidity and mortality for women in the US and worldwide. There have been significant improvements in cardiovascular mortality in women in the last two decades with narrowing of outcomes between women and men which have been attributed to improved therapy for established cardiovascular disease and to primary and secondary preventive interventions. However, women are less likely to receive evidence-based care and have worse outcomes than men. Gender differences have been recognized, but vast knowledge gaps in gender differences regarding pathophysiology, clinical presentation, diagnosis, and optimal acute and chronic treatment strategies for heart attacks and co-existing or resulting complications such as heart failure remain. The AHA Scientific Statement “Acute Myocardial Infarction in Women” provides a comprehensive review of the current evidence.
 
At the opening plenary session of the American College of Cardiology ACC.18 meeting in Orlando, Florida, the pioneer of women’s cardiology Dr. Nanette Kass Wenger gave her inspiring Simon Dack keynote lecture on Heart Disease & Women titled “Understanding the Journey-The Past, Present and Future of CVD in Women.”
 
In “Steps on the journey” Dr. Wenger gave a comprehensive review of the early beginnings and showed how far we have come. Some interesting anecdotes were also shared such as that the first women’s heart disease meeting in Iowa in the 1950s was to help women prevent heart attacks in husbands.
 
Her impactful vision on how to expand the landscape of women’s cardiovascular health research in the next decade struck a nerve with me and made me re-think some of the concepts we are applying in academic cardiology. Dr. Wenger called for an expansion of women’s cardiovascular health research to include social determinants of health as nearly 80% of heart outcomes depend on social factors. Women’s Heart Health is not solely a medical problem and clinical research cannot happen in a vacuum in the hospital. A variety of factors contribute to women’s cardiovascular health and need to be considered for maintenance of health and cure of disease. Women’s Heart Heath needs to be extended. Factors like beliefs and behaviors, the local community, economic, environmental, ethical, legislative/political, public policy – all these social determinants need to be included in heart disease research in women.
 
My take away for the future was that we cannot longer compartmentalize and that programs focusing on Women’s Heart Heath need to involve all programs available- not only cardiology. It needs to be an interdisciplinary approach to learn more about physiology, psychology and ecology of health for best outcomes and to tackle Women’s Heart Health.
 
Dr. Wenger quoted the French Victor Hugo in her inspiring lecture.
 
“There is nothing as powerful as an idea whose time has come.”
Victor Hugo
Histoire d’un crime, 1977
 

Tanja Dudenbostel Headshot

Tanja Dudenbostel is an Internist, Hypertension Specialist within Cardiology at the University of Alabama at Birmingham where I divide my time as an Assistant Professor between clinical research and seeing patients in cardiology.