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The Clock is Ticking: Door-to-Needle Time in Acute Ischemic Stroke

Lay of the Land

In 2008, after years of being the third-leading cause of death in the United States, stroke dropped to fourth. In part, this reflected the results of a commitment made by the American Heart Association/American Stroke Association (AHA/ASA) more than a decade prior to reduce stroke, coronary heart disease, and cardiovascular risk by 25% by the year 2010 (a goal met a year early in 2009). The reason for the success, although multifactorial, can largely be attributed to improved prevention and improved care within the first hours of acute strokes.1 As early as 2000, the benefits of time-dependent administration of intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke were well supported (Figure 1).2

Figure 1. Graph of model estimating OR for favorable outcome at 3 months in recombinant tissue-type plasminogen activator (rt-PA) treated patients compared to placebo treated patients by time from stroke onset to treatment (onset-to-treatment time [OTT]) with 95% confidence intervals, adjusting for the baseline NIH Stroke Scale. OR > 1 indicates greater odds that rt-PA treated patients will have a favorable outcome at 3 months compared to the placebo treated patients. Range of OTT was 58 to 180 minutes with mean (μ) of 119.7 minutes.2

Guidelines began recommending a door-to-needle time for tPA administration of 60 minutes or less, however, studies found that less than 30% of US patients were treated within this time window. The Target: Stroke initiative was launched in 2010 to assist hospitals in providing timely tPA. As a result, the proportion of tPA administered within 60 minutes increased from 26.5% during the preintervention period to 41.3% after implementation. Despite national initiatives, shorter door-to-needle times have not been as quickly adopted as door-to-balloon times for percutaneous coronary intervention in acute coronary syndromes (Figure 2).4 Part of the problem is a lack of robust mortality outcomes data to support trends observed in the (only) two randomized trials conducted to assess long term outcomes with tPA in acute ischemic stroke; neither of which was powered to probe for mortality effects.

Figure 2. Trend in percentage of patients with door-to-balloon (D2B) time <90 minutes over 6 years.4

This brings us to the study published earlier this week in JAMA Man S et al. (corresponding author Fonarow GC) titled “Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke.” This nationwide study of US patients treated with intravenous tPA for acute ischemic stroke demonstrated that shorter door-to-needle times were significantly associated with better long-term outcomes, including lower 1-year all-cause mortality, 1-year all-cause readmission, and the composite of all-cause mortality or readmission at 1 year.5

Study Design

This US cohort included Medicare beneficiaries aged 65 years or older who were treated with intravenous tPA for acute ischemic stroke at Get With The Guidelines (GWTG)–Stroke participating hospitals between January 1, 2006, and December 31, 2016, with 1-year follow-up through December 31, 2017. Patient clinical data were obtained from the GWTG-Stroke database. Study entry criteria required patients to (1) have been aged 65 years or older; (2) have a discharge diagnosis of acute ischemic stroke; (3) have been treated with intravenous tPA within 4.5 hours of the time they were last known to be well; (4) have had a documented door-to-needle time; (5) not have been treated with a concomitant therapy with intra-arterial reperfusion techniques; (6) have had the admission be the first for stroke during the study period; and (7) not have been transferred to another acute care hospital, left against medical advice, or without a documented site of discharge disposition.5 Overall, 61426 participants met the inclusion criteria for the study.

The prespecified primary outcomes included 1-year all-cause mortality, 1-year all-cause readmission, and the composite of all-cause mortality or readmission at 1 year. One-year cardiovascular readmission was a prespecified secondary outcome and was defined as a readmission with a primary discharge diagnosis of hypertension, coronary artery disease, myocardial infarction, heart failure, abdominal or aortic aneurysm, valvular disease, and cardiac arrhythmia. Recurrent stroke readmission, a post hoc secondary outcome, was defined as a readmission for transient ischemic attack, ischemic and hemorrhagic stroke, carotid endarterectomy or stenting, but not for direct complications of index stroke.5

Door-to-needle time was first analyzed using the prespecified times of within 45 minutes and within 60 minutes versus longer than those targets, in line with prior studies on this topic. The authors also ingeniously also evaluated time as a continuous variable, as a categorical variable in 15-minute increments using within 30 minutes as the reference group, and in 45-minute and 60-minute increments. Cox proportional hazards models were used to examine the associations of door-to-needle timeliness and each 1-year outcome with robust variance estimation to ac- count for the clustering of patients within hospitals.5 On hours were defined as 7:00 AM to 6:00 PM on any weekday. Off hours were defined as any other time, including evenings, nights, weekends, and national holidays. The authors did this because prior studies using this prespecified time cutoff have shown that presenting during off hours was associated with inferior quality of care, inferior intravenous thrombolytic treatment, and in-hospital mortality.5

Results

Among the 61426 Medicare beneficiaries treated with intravenous tPA within 4.5 hours of the time they were last known to be well at the 1651 GWTG-Stroke participating hospitals, the median age was 80 years, 43.5% were male, 82.0% were non-Hispanic white, 8.7% were non-Hispanic black, 4.0% were Hispanic, and 5.3% were of other race/ethnicity. More patients that arrived during off hours were treated within longer door-to-needle times (40.7% for ≤30 minutes, 45.6% for 31-45 minutes, 50.6% for 46-60 minutes, 53.5% for 61-75 minutes, and 56.3% for >75 minutes; P < .001). Despite having longer onset-to-arrival times, some patients had shorter onset-to-needle and door-to-needle times.5

Most patients were treated at teaching hospitals (77.7%) and primary stroke centers (73.2%); 3% were treated at rural hospitals. More patients who were treated at teaching hospitals, but not at primary stroke centers, were treated within shorter door-to-needle times. The median door-to-needle time was 65 minutes, with 5.6% of patients treated with tPA within 30 minutes of hospital arrival, 20.8% within 45 minutes, and 44.1% within 60 minutes.5

Patients who received tPA after 45 minutes of hospital arrival had worse long-term outcomes than those treated within 45 minutes of hospital arrival, including significantly higher all-cause mortality (35.0% vs 30.8%, respectively; adjusted hazard ratio [HR], 1.13 [95% CI, 1.09- 1.18]), higher all-cause readmission (40.8% vs 38.4%; ad- justed HR, 1.08 [95% CI, 1.05-1.12]), higher all-cause mortality or readmission (56.0% vs 52.1%; adjusted HR, 1.09 [95% CI, 1.06-1.12]), and higher cardiovascular readmission (secondary outcome) (19.8% vs 18.4%; adjusted HR, 1.05 [95% CI, 1.00- 1.10]), but not significantly higher recurrent stroke readmission (a post hoc secondary outcome) (9.3% vs 8.8%; adjusted HR, 1.05 [95% CI, 0.98-1.12]).

Patients who received tPA after 60 minutes of hospital arrival vs within 60 minutes of hospital arrival had significantly higher adjusted all-cause mortality (35.8% vs 32.1%, respectively; adjusted HR, 1.11 [95% CI, 1.07-1.14]), higher all-cause readmission (41.3% vs 39.1%; adjusted HR, 1.07 [95% CI, 1.04-1.10]), higher all-cause mortality or readmission (56.8% vs 53.1%; adjusted HR, 1.08 [95% CI, 1.05-1.10]), and higher cardiovascular readmission (secondary outcome) (20.2% vs 18.6%; adjusted HR, 1.06 [95% CI, 1.01-1.10]), but not significantly higher recurrent stroke readmission (a post hoc secondary outcome) (9.3% vs 8.9%; adjusted HR, 1.03 [95% CI, 0.97-1.09]).

The absolute differences in outcomes increased with longer door-to-needle times. The cumulative incidence curves showed that approximately 42% of the deaths or readmissions occurred within 30 days.

Every 15-minute increase in door-to-needle times was significantly associated with higher all-cause mortality (adjusted HR, 1.04 [95% CI, 1.02-1.05] for door-to-needle time within 90 minutes of arrival. However, this association did not persist beyond 90 minutes of hospital arrival. Every 15-minute increase in door-to-needle times was significantly associated with higher all-cause readmission (adjusted HR, 1.02 [95% CI, 1.01- 1.03]) and higher all-cause mortality or readmission (adjusted HR, 1.02 [95% CI, 1.01-1.03]). Every 15-minute increase in door-to-needle times after 60 minutes of hospital arrival was significantly associated with higher cardiovascular readmission (secondary outcome) (adjusted HR, 1.02 [95% CI, 1.01- 1.04]) and higher stroke readmission (a post hoc secondary out- come) (adjusted HR, 1.02 [95% CI, 1.00-1.04]); however, these associations were not statistically significant for the door-to-needle times within 60 minutes of hospital arrival.

My Take

I would first like to commend the authors on this undertaking. The fact that early door-to-balloon time is still questionable seems contrary to our understanding of ischemic events and time to cell necrosis. This high-quality study further supports the notion that “time is muscle,” as seen in other ischemic events such as acute myocardial infarction and acute limb ischemia. However, the limitations of the study affects its generalizability and application to real world scenarios. The patients in this study are all over the age of 65, largely non-Hispanic whites, all with recorded times of last seen normal and mostly treated in academic centers with stroke units. Nonetheless, the authors have certainly progressed the field of stroke treatment, if even incrementally, in the right direction.

References:

  1. Jauch EC, Saver  JL, Adams  HP  Jr,  et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology.  Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2013;44(3):870-947.
  2. Marler JR, Tilley  BC, Lu  M,  et al.  Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.  Neurology. 2000;55(11):1649-1655.
  3. Fonarow GC, Zhao X, Smith EE, et al. Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA. 2014;311(16):1632- 1640. doi:10.1001/jama.2014.3203
  4. Krumholz HM, et al. Improvements in door-to-balloon time in the United States, 2005-2010. Circulation 2011;124:1038-45.
  5. Man S, Xian Y, Holmes DN, et al. Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke. JAMA. 2020;323(21):1-15. doi:10.1001/jama.2020.5697

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Hypertension and Stroke: Current State of Evidence

Stroke is the fifth leading cause of death in the country and the top reason for adult disability (1). Each year about 795,000 people experience a stroke in the United States with nearly 25% of these strokes being recurrent events in people with a prior history of a stroke (2).  Hypertension is the considered to be the most important modifiable risk factor for stroke. Therefore, treatment of hypertension is one of the most effective strategies for primary and secondary prevention of stroke (3). In a large meta-analysis from 2002, which included 1 million patients, a direct association was seen between blood pressure measurements and risk of vascular mortality including stroke and ischemic heart disease (4). There is a continuous relationship with risk throughout the normal range of blood pressure, down at least as far as 115/75 mm Hg according to this meta-analysis of 61 prospective clinical studies. However, there has been a lack of consensus among experts about the most appropriate blood pressure targets for cardiovascular disease and stroke prevention.

In the Secondary Prevention of Small Subcortical Strokes (SPS-3) trial, investigators compared systolic blood pressure targets of 130-149 mm Hg and less than 130 mm Hg (5). About 3000 patients with a recent history of an MRI confirmed lacunar stroke were randomized to one of the two treatment groups and followed for a mean of 3.7 years. Primary outcome of recurrent stroke was seen at a lower rate in the lower target group with an annualized stroke rate of 2.25% as compared to 2.77% in the higher target group. Despite a signal toward benefit of a lower BP target, these results did not reach statistical significance. The rates of intracerebral hemorrhage were noted to be significantly lower with a lower BP target.

In a clinical trial enrolling patients with diabetes and a high cardiovascular risk, blood pressure target of less than 120 mm Hg was not superior to a target of less than 140 mm Hg for reducing risk of cardiovascular events with the exception of stroke (6). In this study, the intensive blood pressure target lead to a significant risk reduction for stroke but not for myocardial infarction or all-cause mortality.

To further ascertain an ideal blood pressure target, investigators in the SPRINT trial enrolled over 9000 persons with SBP of more than 129 mm Hg without a history of diabetes (7). The participants were randomized to intensive treatment (target <120 mm Hg) or standard treatment groups (target <140 mm Hg). Primary outcome was a composite of myocardial infarction, heart failure, stroke or vascular death. After a median follow up of 3.3 years, the trial was stopped early due to a significantly lower rate of primary composite outcome in the intensive blood pressure group as compared to the standard treatment. Interestingly, even though there was a signal of benefit for stroke risk reduction, this was not statistically significant. The investigators of the study make note of this finding and hypothesize that this could be due to the fact that this trial excluded patients with a prior history of stroke and TIA. This has also raised questions about the limited applicability of these results to patients with a history of stroke.

The investigators also looked at cognitive outcomes for the two groups of patients in this trial (8). The composite outcome of mild cognitive impairment and dementia was seen in a significantly lower number of patients in the intensive BP treatment group as compared to the standard treatment group. Due to the early termination of SPRINT, the study was underpowered to show a significant difference in the risk of dementia.

The current guidelines (9) from the American Heart Association/ American College of Cardiology recommend initiating treatment at SBP>130 mm Hg for patients with a high cardiovascular risk. Using the current definition of hypertension, it is estimated that 46% of adults in the US have hypertension and about 36% should be prescribed antihypertensive medications (10). Applying these new guidelines, only about half of all US adults on medications for hypertension are currently below the target BP numbers.

With hypertension playing such an important role in the development of the two most common neurological illnesses (Stroke and cognitive disorders), authors of a recent paper in JAMA Neurology (11) urge neurologists to play a greater role in treatment of hypertension as a preventive strategy for their patients. Traditionally stroke neurologists and neurointensivists have been involved in treatment of the cardiovascular risk factors including hypertension but most of that is done after the patient has had a major event such as an ischemic stroke or intracerebral hemorrhage. The authors argue that neurologists should participate in treatment of hypertension for their patients as a primary preventive strategy as it would lead to an overall improved brain health of our ageing population.

To learn more about the latest advancements in the field of hypertension research, I encourage the readers to attend Hypertension 2019 Scientific Sessions being held in New Orleans September 5-8, 2019.

 

References:

  1. Vital Signs: Recent trends in stroke death rates – United States, 2000-2015. MMWR 2017;66.
  2. Benjamin EJ, Blaha MJ, Chiuve SE, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135:e229-e445.
  3. Katsanos AH, Filippatou A, Manios E, et al. Blood pressure reduction and secondary stroke prevention: a systematic review and metaregression analysis of randomized clinical trials. Hypertension. 2017;69(1):171-179.
  4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies Lancet. 2002;360(9349):1903-1913.
  5. Benavente OR, Coffey CS, Conwit R, et al; SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-515.
  6. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-1585
  7. Wright JT  Jr, Williamson  JD, Whelton  PK,  et al; SPRINT Research Group.  A randomized trial of intensive versus standard blood-pressure control  [published correction appears in N Engl J Med. 2017;377(25):2506].  N Engl J Med. 2015;373(22):2103-2116.
  8. Williamson JD, Pajewski NM, Auchus AP, et al; SPRINT MIND Investigators for the SPRINT Research Group. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial.JAMA. 2019;321(6):553- 561
  9. Whelton PK, Carey RM, Aronow WS, et al.
  10. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-e248.
  11. Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. Circulation. 2018;137(2): 109-118.
  12. Betjemann J, Hemphill JC, Sarkar U. Time for Neurologists to Drop the Reflex Hammer on Hypertension. JAMA Neurol.Published online August 19, 2019. doi:10.1001/jamaneurol.2019.2588
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Race and In-Hospital Stroke Care

Intracerebral haemorrhage [ICH] accounts for ~15% of all strokes with an estimated 40% mortality at one month, with higher rates of occurrence among Black patients1. Differences have been observed in the burden of ICH by race, with a higher incidence among Black, Asian and Hispanic compared to White patients2,3.

The number of hospital admissions for ICH in the United States escalated from 150,000 in early 1990s to 175,000 in early 2000s2. Studies have reported racial differences in the quality and process of care among patients hospitalized with ICH4. A recent paper by Cruz-Flores found racial differences in In-hospital utilization of care including lifesaving and life-sustaining therapies, palliative care, do not resuscitate status and in-hospital mortality5.

Two recent studies showed that compared to whites, minority patients were more often younger with higher rates of medical comorbidities, longer length of stay and lower rates of do not resuscitate orders and in-hospital mortality2,5. Rates of hospital admissions have been also shown to be higher among minority men compared to women, however this might be a mere reflection of females not having equal access to care5.

A report on stroke performance measures by Xian in 2014 revealed smoking cessation counselling was less frequently completed among minority patients2. Counseling on modifiable risk factors is a key measure to reduce risk of stroke, recurrent stroke and coronary heart disease. In addition, Xian et al reported that Black patients were less likely than White patients to have a door to CT time of ≤ 25 minutes2. Rapid neuroimaging is one of the key class I recommendations of the American Heart Association/American Stroke Association for ICH patients2,6. Subsequent management is essentially dependent on identification of stroke subtype by neuroimaging. Further research is needed to identify mechanisms and causes of disparities in outcomes after stroke, ICH in particular, among minority patients.

 

REFERENCES

  1. Kleindorfer D, Khoury J, Moomaw CJ, Alwell K, Woo D, Flaherty ML, Khatri P, Adeoye O, Ferioli S, Broderick JP, Kissela BM. Stroke incidence is decreasing in whites, but not in blacks: a population-based estimate of temporal trends in stroke incidence from the Greater Cincinnati/Northern Kentucky stroke study. Stroke; a journal of cerebral circulation. 2010 Jul;41(7):1326.
  2. Xian Y, Holloway RG, Smith EE, et al. Racial/ethnic differences in process of care and outcomes among patients hospitalized with intracerebral hemorrhage. Stroke 2014; 45: 3243–3250.
  3. Woo D, Rosand J, Kidwell C, et al. The ethnic/racial variations of intracerebral hemorrhage (ERICH) study protocol. Stroke 2013; 44: e120–e125.
  4. Cruz-Flores S, Rabinstein A, Biller J, et al. Racial-ethnic disparities in stroke care: the American experience: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: 2091–2116.
  5. Cruz-Flores, Salvador, Gustavo J. Rodriguez, Mohammad Rauf A. Chaudhry, Ihtesham A. Qureshi, Mohtashim A. Qureshi, Paisith Piriyawat, Anantha R. Vellipuram, Rakesh Khatri, Darine Kassar, and Alberto Maud. “Racial/ethnic disparities in hospital utilization in intracerebral hemorrhage.” International Journal of Stroke (2019): 1747493019835335.
  6. Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, et al; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010; 41:2108–2129.

 

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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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Success Does Not Always Leave A ‘Footprint’

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

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!!!

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?

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?

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.Chest138(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.Circulation129(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.Jama316(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 cardiology1(1), 55-62.

 

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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.