Extended-Window Thrombolysis Improves Stroke Outcomes with increased bleeding risk: JAMA

 Will your competent? doctor and hospital ENSURE FURTHER RESEARCH OCCURS that will determine the best way to prevent the bleeding risk? Oh NO; the plan is TO DO NOTHING!  Everyone there needs to be fired! I take no prisoners in trying to get stroke solved!

Extended-Window Thrombolysis Improves Stroke Outcomes with increased bleeding risk: JAMA

Late-Window Tenecteplase Improves Functional Outcomes but Increases Bleeding Risk in Non-Large Vessel Ischemic Stroke: JAMA

 The survivor wouldn't need to take this risk if you CREATED 100% RECOVERY PROTOCOLS regardless of time presented! 

If Pedro Bach-y-Rita can fully recover with only a partial brain then our stroke medical 'professionals' can duplicate that! Way back in 1958 so plenty of time to analyze and create 100% recovery protocols!

No knowledge and doing nothing IS PURE INCOMPETENCE!

Pedro Bach-y-Rita (14 posts to May 2011)

Late-Window Tenecteplase Improves Functional Outcomes but Increases Bleeding Risk in Non-Large Vessel Ischemic Stroke: JAMA

Development of a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy

Finally some research on predicting gastrointestinal bleeding. Now if we had some stroke leadership, we could predict gastrointestinal bleeding from aspirin alone! But since there is NO leadership, nothing will occur!

 Development of a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy

Yuncao Fan¹Chunping Zhu²Jiamei Zhou²Renjie Yi²Jiaming Huang^2*

• ¹Department of Cardiovascular, The First People’s Hospital of Wenling, Wenling, Zhejiang, China
• ²Department of Gastroenterology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, China

Objective: To establish a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy (DAPT).

Methods: A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established based on a retrospective study that involved 1,217 patients diagnosed with ischemic stroke in the Neurology Department of Nanchang University Affiliated Ganzhou Hospital from January 2019 to June 2021. A receiver operating characteristic curve was constructed to evaluate the model’s power. Data from patients with ischemic stroke between July and December 2021 were used to validate the power of the model.

Results: A total of 1,217 patients with ischemic stroke between January 2019 and June 2021 were included in the model. The cohort comprised 1,164 patients in the non-gastrointestinal bleeding group and 53 in the gastrointestinal bleeding group. Multivariate logistic regression analysis revealed that age, fibrinogen level, neutrophil-to-lymphocyte ratio, and National Institute of Health Stroke Scale score were independent risk factors for gastrointestinal bleeding. A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established, Logit(P) = −7.269 + 0.074 ×1 + 0.071 ×2 + 0.361 ×3 + 0.082 ×4 (X1, National Institute of Health Stroke Scale score; X2, neutrophil-to-lymphocyte ratio; X3, fibrinogen; X4, activated partial thromboplastin time). Receiver operating characteristic analysis showed that the area under the curve for the model was 0.733. Data from the validation group showed that the area under the curve for the model was 0.665.

Conclusion: A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established and demonstrated its predictive ability. Although the predictive ability of the model was not perfect, this was an important attempt. Further studies are needed to establish better models to predict gastrointestinal bleeding.

1 Introduction

Ischemic stroke is a serious neurological dysfunction caused by insufficient cerebral blood supply. It is a leading cause of death and disability worldwide (1). In 2021, there were 11.9 million incident strokes globally, and 65.3% of which were ischemic (2). Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is effective in reducing recurrent ischemic stroke, but increases the risk of gastrointestinal bleeding. Risk factors for gastrointestinal bleeding in patients with ischemic stroke after DAPT includes stroke severity and neutrophil-to-lymphocyte ratio (NLR) (3, 4). Because gastrointestinal bleeding is a risk factor for increased mortality in acute cerebral infarction (5), predicting its occurrence in patients with ischemic stroke after DAPT is crucial. However, a predictive model for this specific population is currently lacking. Therefore, we retrospectively analyzed the data of patients with ischemic stroke receiving DAPT at the Nanchang University Affiliated Ganzhou Hospital to develop a model for predicting gastrointestinal bleeding.

More at link

Development of a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy

You probably want your competent? doctor using this on you.

Dual antiplatelet therapy (DAPT) involves using two different antiplatelet medications to reduce the risk of blood clots, heart attack, and stroke. Typically, it combines aspirin with a P2Y12 inhibitor like clopidogrel, prasugrel, or ticagrelor.

The latest here:

 Development of a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy

Yuncao Fan1, Chunping Zhu2, Jiamei Zhou2, Renjie Yi2 and Jiaming Huang2*

1Department of Cardiovascular, The First People’s Hospital of Wenling, Wenling, Zhejiang, China

2Department of Gastroenterology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, China

Edited by

Reza Dashti, Stony Brook Medicine, United States

Reviewed by

Jingxin Wang, Stony Brook Medicine, United States

Jason Mathew, Stony Brook Medicine, United States

*Correspondence

Jiaming Huang, victor471842@126.com

Received 10 February 2025

Accepted 01 May 2025

Published 18 June 2025

Citation

Fan Y, Zhu C, Zhou J, Yi R and Huang J (2025) Development of a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy. Front. Neurol. 16:1574278. doi: 10.3389/fneur.2025.1574278

Objective: 

To establish a model for predicting gastrointestinal bleeding in patients with ischemic stroke after dual antiplatelet therapy (DAPT).

Methods: 

A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established based on a retrospective study that involved 1,217 patients diagnosed with ischemic stroke in the Neurology Department of Nanchang University Affiliated Ganzhou Hospital from January 2019 to June 2021. A receiver operating characteristic curve was constructed to evaluate the model’s power. Data from patients with ischemic stroke between July and December 2021 were used to validate the power of the model.

Results: 

A total of 1,217 patients with ischemic stroke between January 2019 and June 2021 were included in the model. The cohort comprised 1,164 patients in the non-gastrointestinal bleeding group and 53 in the gastrointestinal bleeding group. Multivariate logistic regression analysis revealed that age, fibrinogen level, neutrophil-to-lymphocyte ratio, and National Institute of Health Stroke Scale score were independent risk factors for gastrointestinal bleeding. A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established, Logit(P) = −7.269 + 0.074 ×1 + 0.071 ×2 + 0.361 ×3 + 0.082 ×4 (X1, National Institute of Health Stroke Scale score; X2, neutrophil-to-lymphocyte ratio; X3, fibrinogen; X4, activated partial thromboplastin time). Receiver operating characteristic analysis showed that the area under the curve for the model was 0.733. Data from the validation group showed that the area under the curve for the model was 0.665.

Conclusion: 

A model for predicting gastrointestinal bleeding in patients with ischemic stroke after DAPT was established and demonstrated its predictive ability. Although the predictive ability of the model was not perfect, this was an important attempt. Further studies are needed to establish better models to predict gastrointestinal bleeding.

Keywords

ischemic stroke; dual antiplatelet therapy; gastrointestinal bleeding; risk factor; model

1 Introduction

Ischemic stroke is a serious neurological dysfunction caused by insufficient cerebral blood supply. It is a leading cause of death and disability worldwide (1). In 2021, there were 11.9 million incident strokes globally, and 65.3% of which were ischemic (2). Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is effective in reducing recurrent ischemic stroke, but increases the risk of gastrointestinal bleeding. Risk factors for gastrointestinal bleeding in patients with ischemic stroke after DAPT includes stroke severity and neutrophil-to-lymphocyte ratio (NLR) (3, 4). Because gastrointestinal bleeding is a risk factor for increased mortality in acute cerebral infarction (5), predicting its occurrence in patients with ischemic stroke after DAPT is crucial. However, a predictive model for this specific population is currently lacking. Therefore, we retrospectively analyzed the data of patients with ischemic stroke receiving DAPT at the Nanchang University Affiliated Ganzhou Hospital to develop a model for predicting gastrointestinal bleeding.

More at link.

Abelacimab reduces bleeding risk compared to rivaroxaban in atrial fibrillation

 Your competent? doctor is current on all research and implements it immediately, right? NO? So, you DON'T have a functioning stroke doctor, do you? 

Abelacimab reduces bleeding risk compared to rivaroxaban in atrial fibrillation

byZhenyu LiandKiera Liblik

March 7, 2025

in Cardiology, Chronic Disease, Emergency, Surgery Classics, The 2MM Team, The Classics

Reading Time: 2 mins read

1. In this randomized controlled trial, abelacimab led to significantly lower rates of major or clinically relevant nonmajor bleeding compared to rivaroxaban in patients with atrial fibrillation at moderate-to-high stroke risk.

2. Abelacimab led to significantly reduced free factor XI levels compared to rivaroxaban. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Atrial fibrillation has a high prevalence and considerably increases the risk of stroke five-fold. Accordingly, those with atrial fibrillation commonly take anticoagulation agents to prevent thromboembolic events. These include direct oral anticoagulants such as rivaroxaban. However, there are significant bleeding risks associated with these medications even though they are safer than previous therapies like warfarin. Accordingly, factor XI-targeted therapy is being explored as a method for reducing stroke risk in atrial fibrillation patients. This phase 2b, multinational RCT (AZALEA-TIMI 71) assessed the safety of abelacimab, a factor XI inhibitor, in anticoagulation therapy for atrial fibrillation. The study was halted early due to a substantial reduction in bleeding events in the abelacimab groups. While abelacimab demonstrated a significant decrease in bleeding compared to rivaroxaban, ischemic stroke incidence was slightly higher in the abelacimab groups, though not statistically significant. The study suggests abelacimab may be a safer alternative for patients at risk of anticoagulant-associated bleeding. Limitations include its open-label design for treatment assignment and the need for larger trials to confirm efficacy in stroke prevention.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This multicenter, phase 2b, partially blinded RCT enrolled 1,287 patients with atrial fibrillation and a CHA2DS2-VASc score of ≥3. Patients were randomized in a 1:1:1 ratio to receive either subcutaneous abelacimab at 90 mg or 150 mg once monthly or oral rivaroxaban 20mg once daily (15 mg for patients with creatinine clearance ≤50 ml/min). The study aimed to assess safety outcomes, specifically major or clinically relevant nonmajor bleeding. At three months, the median reduction in free factor XI levels was 99% (interquartile range [IQR] 98–99) with 150 mg and 97% ([IQR] 51–99) with 90 mg of abelacimab. The trial was terminated early due to a significant reduction in major or clinically relevant nonmajor bleeding events in the abelacimab groups compared to rivaroxaban. The bleeding incidence rate was 3.2 events per 100 person-years for the 150 mg group and 2.6 events per 100 person-years for the 90 mg group, compared to 8.4 events per 100 person-years in the rivaroxaban group (Hazards Ratio [HR] 0.38; 95% Confidence Interval [CI], 0.24–0.60) for 150 mg vs. rivaroxaban, ([HR] 0.31; [CI], 0.19–0.51) for 90 mg vs. rivaroxaban, P<0.001 for both). Notably, gastrointestinal bleeding was markedly lower in the abelacimab groups (0.5% vs. 4.2% with rivaroxaban). However, the stroke incidence was slightly higher in the abelacimab groups (1.2% and 1.4% per year for 150 mg and 90 mg, respectively) than in the rivaroxaban group (0.8% per year), though the difference was not statistically significant. Overall, abelacimab demonstrated a strong safety profile with significantly lower bleeding risk than rivaroxaban, highlighting its potential as an alternative anticoagulant.

DAPT Stays Helpful for Minor Stroke Even With Later Presentation, Worse Symptoms

 FYI.  Discuss with your doctors to see what they are doing to reduce the risk of bleeds.

DAPT Stays Helpful for Minor Stroke Even With Later Presentation, Worse Symptoms

But a signal of excess bleeding is noted in the INSPIRES trial

by Nicole Lou, Senior Staff Writer, MedPage Today December 27, 2023

The benefit of dual antiplatelet therapy (DAPT) for a minor ischemic stroke seems to apply outside the 24-hour time window and minimal stroke symptoms for which the treatment is currently recommended, based on results from the INSPIRES trial.

Administered within 72 hours after onset of mild ischemic stroke or high-risk transient ischemic attack (TIA), the combination of clopidogrel (Plavix) plus aspirin resulted in a decrease in any new stroke within 90 days compared with aspirin alone (7.3% vs 9.2%; HR 0.79, 95% CI 0.66-0.94).

The downside was a doubling in moderate-to-severe bleeding at 90 days (0.9% vs 0.4%; HR 2.08, 95% CI 1.07-4.04), reported Yilong Wang, MD, PhD, of Beijing Tiantan Hospital in China, and colleagues in the New England Journal of Medicine.

"The results of our trial potentially broaden the time window for the initiation of treatment, although there was more bleeding with the dual regimen than with the monotherapy," the INSPIRES authors concluded.

For their trial, Wang and colleagues enrolled people with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5) and high-risk TIA (score of 4 or higher on the ABCD² [age, blood pressure, clinical features, duration of symptoms, and presence of diabetes] scale), which marks a step up from the NIHSS threshold of ≤3 that had been used in the POINT and CHANCE trials that established DAPT's benefit for secondary stroke prevention.

INSPIRES also expanded the pool of patients receiving DAPT by testing it within 72 hours. POINT and CHANCE had tested this therapy within 12 and 24 hours, respectively, as this early period is thought to carry the highest risk of recurrent stroke.

Based on these two older trials, the American Heart Association in 2019 updated its guidelines with a class Ia recommendation for a 21-day course of aspirin plus clopidogrel starting within 24 hours for patients with noncardioembolic ischemic stroke and NIHSS scores of 3 or less who didn't get IV thrombolytics.

With the addition of INSPIRES, there is evidence to support expanding the time window for DAPT to 72 hours, commented Anthony Kim, MD, of University of California, San Francisco.

"This timing should nevertheless be interpreted as 'as soon as possible, but within 72 hours' and still necessitates a loading dose of clopidogrel, since its omission would be akin to delaying treatment," Kim urged in his accompanying editorialopens in a new tab or window.

"Overall, for every 1,000 patients with TIA or mild stroke who were treated with clopidogrel–aspirin, approximately 19 fewer strokes and 5 additional moderate-to-severe bleeding events would be expected as compared with aspirin alone, by my rough calculation," he wrote.

For now, DAPT appears to be underutilized in practice: a recent study found that from 2018 to 2021, just over 40% of stroke patientsopens in a new tab or window with an NIHSS score of 3 or less were prescribed DAPT after minor stroke or transient ischemic attack in a population-based registry from the University of Maryland Medical System.

INSPIRES was a double-blind 2x2 factorial trial conducted at 222 hospitals in China.

Participants were 6,100 people with mild ischemic stroke or high-risk TIA -- largely the former -- presumably caused by atherosclerotic stenosis of extracranial or intracranial artery ipsilateral to the ischemic field, or multiple infarctions with nonstenotic atherosclerotic plaque ipsilateral to the ischemic field.

Study protocol had people randomly assigned within 72 hours after symptom onset to DAPT with clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100-300 mg on day 1 and 100 mg daily on days 2 to 21) or aspirin plus placebo.

The cohort had a median age of 65 years, with just over 35% women. Three in four individuals had a NIHSS ≤3, and the remaining quarter had severity scores reach 4 or 5. Approximately 13% of patients were treated within 24 hours of stroke onset.

Subgroup analysis suggested that DAPT prevented recurrent strokes mainly in people randomized between 48 hours and 72 hours -- no earlier.

Additionally, the risk of any bleeding was higher in the clopidogrel-aspirin group (3.1% vs 2.1%, HR 1.50, 95% CI 1.09-2.06).

"This bleeding signal is a reminder that the appropriate duration of dual antiplatelet therapy to balance early benefit and bleeding risk seems to be approximately 21 days and that long-term use of clopidogrel-aspirin is not recommended, given that this approach has not proved beneficial and almost certainly increases bleeding risk," Kim noted.

Chief among the limitations of INSPIRES was a selected cohort that excluded people with presumed cardioembolic TIA or ischemic stroke, people with moderate or severe stroke, patients already on DAPT or intensive statin therapy before the trial, and those who had undergone thrombolysis or thrombectomy. Results may have limited generalizability given a study population that was predominantly Han Chinese.

Furthermore, other antiplatelet regimens were not studied in this trial.

"The incremental expansion of indications for [DAPT] that was shown in this trial is welcome. Perhaps new, more targeted antithrombotic agents on the horizon may hold promise for delivering an even more favorable balance of benefits and risks among patients with stroke," Kim wrote.

• 

  Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

Disclosures

The trial was supported by grants from the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Youth Beijing Scholar Program, the Beijing Talent Project–Class A: Innovation and Development, the National Ten Thousand Talent Plan-Leadership of Scientific and Technological Innovation, Sanofi, and Beijing Jialin Pharmaceuticals.

Wang disclosed institutional grants from Beijing Jialin Pharmaceuticals and Sanofi.

Kim disclosed receiving institutional research grants from the American Heart Association, NIH, and PCORI.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowGao Y, et al "Dual antiplatelet treatment up to 72 hours after ischemic stroke" N Engl J Med 2023; DOI: 10.1056/NEJMoa2309137.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowKim AS "Extending dual antiplatelet therapy for TIA or stroke" N Engl J Med 2023; DOI: 10.1056/NEJMe2311961.

Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE

 You're not solving the correct problem. How do you identify those persons that are at risk of bleeding from aspirin?

Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE

Seniors who took low-dose aspirin daily for primary prevention had no reduction in the risk for first strokes in a large randomized trial that followed them for about 5 years.

But those who took aspirin at 100 mg/d, compared with placebo, did show a significant 38% jump in risk for intracranial (IC) bleeding. Rates for ischemic stroke and for hemorrhagic stroke were similar between the aspirin and control groups.

The excess IC bleeding events included hemorrhagic stroke but also dural and subdural bleeds characteristic of traumatic head injury, such as from falls, researchers say, based on their secondary analysis of the ASPREE trial. The findings applied regardless of age, sex, or cardiovascular (CV) risk factors.

This study, as much as any other, has clouded aspirin's shine as a protectant against CV events in people without a history of stroke or clinical heart disease. It adds to years of randomized trials and meta-analyses suggesting that whatever benefits it may afford in primary prevention are offset by an increased risk for major bleeding.

ASPREE's main clinical outcomes, reported in a barrage of papers in 2018, included failure to show that low-dose aspirin for primary prevention can prolong survival free of physical or mental disability over 5 years. The trial also saw significant associations between daily aspirin and risk for major bleeding, especially upper gastrointestinal bleeding, and death from any cause.

The trial, conducted in Australia and the United States, had entered 19,114 people from the community who were aged 70 years or older or at least 65 for participants in the US identifying as Black or Hispanic.

ASPREE's aspirin recipients experienced 20 fewer ischemic strokes with the trade-off of 29 extra IC bleeding events, notes a report on the secondary analysis published July 26 in JAMA Network Open, with lead author Geoffrey C. Cloud, MB, BS, Monash University, Melbourne, Australia.

Although there were small numbers of hemorrhagic and nonhemorrhagic events in absolute terms, "Numerically, the bleeding events outweighed any possible prevention of ischemic events," senior author John J. McNeil, PhD, from the same institution, told theheart.org | Medscape Cardiology.

Short- vs Long-Term Risks

ASPREE, including a large senior population, combined with the other studies suggesting little or no advantage for aspirin in primary prevention, McNeil observed, "question whether there's much rationale for prescribing it for a long-term benefit, or benefit that might not become apparent for years afterward, when there's so many short-term risks that you have to overcome."

Indeed, ASPREE supports last year's US Preventive Services Task Force's recommendation against routine prescription of low-dose aspirin for primary prevention or any such prescription in adults 60 and older, notes the published report..

A first stroke occurred in 4.7% of aspirin recipients and 4.6% of those on placebo, not a significant difference; nor were there significant differences in rates of ischemic stroke, hemorrhagic stroke, or fatal stroke.

The risks for IC bleeding were 1.1% and 0.8% for aspirin and placebo recipients, respectively (P = .03).

"I think this is part of the puzzle," Jeffrey S. Berger, MD, who was not part of the study, told theheart.org | Medscape Cardiology. It "clearly lays out" the risk for primary prevention aspirin's most dreaded complication, hemorrhagic stroke.

"When you put all the data together, I think aspirin for the prevention of a first heart attack or stroke is marginally effective. But that has to be balanced against the potential risk, and this study clearly illustrates the significance of that risk," said Berger, NYU Langone Hospitals and director of the Center for the Prevention of Cardiovascular Disease at NYU Grossman School of Medicine, New York City.

The benefit of aspirin "is not as high as it once was" in an age when there are so many effective therapies that lower coronary and neurovascular risk, Berger observed. "While its absolute risk is low, the absolute benefit is also pretty low."

For populations that have been studied, he said, "the benefit of aspirin for the prevention of a first heart attack or stroke does not outweigh its risk."

Among the analysis' important features, McNeil said, is its separation of stroke and nonstroke IC bleeding events by their anatomic locations.

An "Unrecognized Risk"

Intracranial bleeds overall as well as subdural, extradural, and subarachnoid bleeds thought to be caused by trauma were more common in the aspirin group. But the differences fell short of significance at such low incidence rates.

Subdural, extradural, and subarachnoid bleeding "are commonly caused by head strikes from falls," for which seniors are more at risk than younger adults, he observed.

"We're highlighting an unrecognized risk of aspirin, this totality of intracranial bleeds," McNeil said. "In older people, we know that bleeding risk is high, and we know the risk of head trauma is high. You put it all together and it's a statistically significant increase that doctors should be aware of."

Of the trial population (56% female, median age 74), 9525 participants were assigned to daily aspirin and 9589 to placebo and followed a median of 4.7 years.

Despite no significant differences for all strokes or ischemic or hemorrhagic stroke separately, hazard ratios for risk for IC bleeding, including hemorrhagic stroke, were significantly increased in the aspirin group and trended up for nonstroke IC bleeding:

• All stroke: 0.97 (95% confidence interval [CI], 0.79 - 1.18; P = .04)

• Ischemic stroke, 0.89 (95% CI, 0.71 - 1.11; P = .28)

• Hemorrhagic stroke, 1.33 (95% CI, 0.87 - 2.04; P = .19)

• All IC bleeding, 1.38 (95% CI, 1.03 - 1.84; P = .03)

• Nonstroke IC bleeding, 1.45 (95% CI, 0.98 - 2.16; P = .07)

"I think the scientific community really has a lot to learn about using precision-based medicine to figure out who should be on a therapy like aspirin," Berger said.

"In my personal opinion," he added, "why is it that — with a drug like aspirin, which we know how it works — we can't measure platelet activity" the way blood pressure and lipids are measured to guide medical therapy?

Berger foresees a time "in the near future when we will be able to measure platelet activity or platelet genetics and tell us who would benefit from a drug like aspirin."

The field doesn't need yet another broad-based primary prevention aspirin trial, he said. "We need to start thinking about how the drug works and choose our populations wisely."

JAMA Network Open. Published online July 26, 2023. Full text

ASPREE was funded by the National Institute on Aging and the National Cancer Institute; the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. McNeil has disclosed no relevant financial relationships. Berger has previously disclosed receiving grants from the National Heart, Lung, and Blood Institute and the American Heart Association, and personal fees from Janssen and Amgen.

 

Research Casts Doubt on Value of Daily Aspirin for Healthy Adults

You're not solving the correct problem. How do you identify those persons that are at risk of bleeding from aspirin?

Research Casts Doubt on Value of Daily Aspirin for Healthy Adults

Daily use of low-dose aspirin offers no significant protection against stroke and was linked to a higher rate of bleeding in the brain, according to new research published in JAMA.

The research matches other evidence advising that healthy older adults without a history of heart conditions or warning signs of stroke should not take low-dose aspirin. 

The findings also support the recommendation from the U.S. Preventive Services Task Force that low-dose aspirin should not be prescribed for preventing a first heart attack or stroke in healthy older adults, The New York Times reported.

"We can be very emphatic that healthy people who are not on aspirin and do not have multiple risk factors should not be starting it now," said Randall Stafford, MD, of Stanford University, who was not involved in the study, in The Times.

It's not as clear for others, he said.

"The longer you've been on aspirin and the more risk factors you have for heart attacks and strokes, the murkier it gets," he said.

Some cardiac and stroke experts say daily aspirin should remain part of the regimen for people who have had a heart attack or stroke.

The JAMA report was based on data from a randomized control trial of 19,000 people from Australia and America. Participants were over the age of 70 and did not have heart disease. 

The data covered an average of almost 4.7 years and revealed that aspirin lowered the rate of ischemic stroke but not significantly(To me any lowering is great, SO SOLVE THE BLEEDING RISK PROBLEM YOU BLITHERING IDIOTS!). An ischemic stroke happens when a clot forms in a blood vessel that sends blood to the brain. 

There was also a 38% higher rate of brain bleeds for people who took aspirin daily compared to those who took a placebo.

The Times wrote, "In the past, some doctors regarded aspirin as something of a wonder drug, capable of protecting healthy patients against a future heart attack or stroke. But recent studies have shown that the powerful drug has limited protective power among people who have not yet had such an event, and it comes with dangerous side effects."

Sources

JAMA: "Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People Secondary Analysis of a Randomized Clinical Trial."

The New York Times: "For Adults With No Heart Attack or Stroke History, Evidence Says Not to Start Baby Aspirin."

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

So now YOU need to find out what the difference is between preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.  I had several Lovenox shots when my INR was out of whack but have no clue if that was
therapeutic or prophylactic.  I'm still going to be requesting heparin or Lovenox shots because I don't want all the microthrombi circulating  in my blood causing all kinds of havoc. But don't listen to me, I'm not medically trained, you'll just have to hope your doctor guesses correctly because there is not enough information yet to create protocols. I suppose you'll just have to wait a couple of years before you get COVID-19 to allow the research to inform practice. 

The latest here:

Preemptive Blood Thinners Tied to More Deaths in Hospitalized COVID-19 Patients

Risk of in-hospital mortality 2.3 times greater versus prophylactic anticoagulation, but many questions remain

by Zeena Nackerdien PhD, CME Writer, MedPage Today 2020-08-05

Study Authors: Jishu K. Motta, Rahila O. Ogunnaike, et al.

Target Audience and Goal Statement: Infectious disease specialists, hematologists, pulmonologists, critical care specialists

The goal of this study was to compare clinical outcomes of patients with COVID-19 who received preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.

Question Addressed:

• What was the impact of preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing on in-hospital mortality among COVID-19 patients?

Study Synopsis and Perspective:

Researchers have sought to examine the possible benefits of using anticoagulants to treat COVID-19 patients, with mixed results. In one study of patients with severe COVID-19, use of prophylactic low-molecular-weight heparin (LMWH) seemed to improve survival compared with no anticoagulation therapy.

Action Points

• Among patients hospitalized with COVID-19, risk of in-hospital mortality was 2.3 times greater in those receiving preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing, according to a study from two acute care U.S. hospitals.
• Note that study limitations included the retrospective study design, lack of randomization, no capture of mortality after the patients left the hospital, unmeasured confounding, and limited generalizability.

In another study, there was no significant change in in-hospital mortality in COVID-19 patients who received anticoagulants compared with those who did not, though a decreased length of hospital stay was noted. In addition, use of anticoagulation was associated with a significant decrease in mortality among mechanically ventilated patients.

In a retrospective study published on the medRxiv preprint server, Jishu Kaul Motta, MD, of Danbury Hospital in Connecticut, and colleagues hypothesized that preemptive treatment with therapeutic anticoagulation could lower the risk of a COVID-19-associated prothrombotic state leading to increased mortality.

However, they observed more deaths among those treated preemptively versus prophylactically with anticoagulants, and they also showed that patients with more severe disease (C-reactive protein ≥200 mg/L) did not experience clinical improvement in outcomes with preemptive therapeutic anticoagulation.

These findings highlight the need to consider the risks and benefits for the patient and the healthcare system when using preemptive therapeutic-dose anticoagulation in hospitalized patients with COVID-19.

Of 501 hospitalized SARS-CoV-2-positive adults across two acute care hospitals located in western Connecticut, 374 patients were included in the study in April 2020, with follow-up through June 12. The study excluded patients who received therapeutic-dose anticoagulation specifically for a thrombotic indication.

Demographic variables were collected via hospital billing inquiries, while clinical variables were taken from patients' medical records.

Patients had an average age of 64.7 years, and men made up more than half of the sample (58.6%). The majority were white (54%); African-Americans constituted 9.9% of the full sample. A third of the patients smoked, and heart disease was the most common comorbidity (56.7%), followed by diabetes (31.6%). The prophylactic and therapeutic anticoagulation groups consisted of 299 and 75 patients, respectively.

The risk of mortality was also determined among 104 patients with C-reactive protein levels ≥200 mg/L.

Most of the patients took enoxaparin(Lovenox) during their inpatient stay (93.5%), and 14.8% took heparin. The prophylactic dosage of enoxaparin was defined as 30 or 40 mg given subcutaneously every day, while the therapeutic dose was defined as 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously daily or based on renal function, or higher doses titrated to an anti-factor Xa range of 0.6 to 1 IU/mL (for twice daily dosing) and 1 to 2 IU/mL (for daily dosing). The prophylactic dosage of heparin was defined as 5,000 units given subcutaneously every 8 hours, and the therapeutic dose was defined as intravenous heparin titrated to an activated partial thromboplastin time between 70 and 110 seconds.

Variables in the full logistic model included anticoagulant dosage, age, ethnicity, diabetes, history of cancer or heart disease, hyperlipidemia, peak C-reactive protein level, and need for intensive care, mechanical ventilation, or use of antibiotics.

Motta and team found that the relative risk of in-hospital mortality was 2.3 times greater (P=0.04) in patients who received preemptive therapeutic-dose anticoagulation compared with standard prophylactic dosing on multivariate analysis, with 38.7 vs 14.4 deaths per 100 patients.

For the patient subgroup with elevated C-reactive protein levels, the researchers found no difference in the risk of mortality between those who received therapeutic versus prophylactic anticoagulation (adjusted risk ratio 1.0, 95% CI 0.2-4.5, P=0.97).

Most patients expired due to worsening oxygenation (71.8%) and acute respiratory failure with hypoxia. Other causes of death included anoxic brain injury due to hemorrhage (n=1), kidney dysfunction with inability to access hemodialysis port (n=1), and failure to thrive with encephalopathy (n=1). Just under two-thirds of patients (64.4%) elected to receive comfort measures only for end-of-life care.

The retrospective study design, lack of randomization, and no capture of mortality after the patients left the hospital were listed as study limitations. Unmeasured confounding and limited generalizability were additional limitations.

Source Reference: medRxiv 2020; DOI: 10.1101/2020.07.20.20147769

Study Highlights and Explanation of Findings:

A retrospective cohort study of hospitalized patients with COVID-19 showed an increase in in-hospital mortality following preemptive therapeutic-dose anticoagulation versus standard prophylactic dosing.

These findings countered those of a larger observational study that suggested better survival with therapeutic anticoagulation in hospitalized COVID-19 patients, although others have suggested no effect.

It was possible that stronger thrombosis prevention is effective but just can't overcome competing risk of death from other disease processes in COVID-19, Motta's group suggested. "Regardless it does not seem from our analyses that therapeutic dosing of anticoagulation prevented overall disease progression," they noted.

However, "any interpretation other than acknowledging the need to study this prospectively in a randomized, controlled trial would be invalid," said Jason Katz, MD, director of cardiovascular critical care at the Duke University Health System in Durham, North Carolina, who was not involved with the study.

Aside from the small size, confounding and bias were also likely due to the "huge differences in patient characteristics between those who got prophylactic-dose anticoagulation and those that got full-dose anticoagulation," Katz pointed out.

Lack of data on bleeding events was another limitation, said Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard University in Boston.

None of the studies done so far are able to really inform practice, he said. "What I do take out from this is the heterogeneity, the variability in the signals, and the effect sizes we keep seeing from these studies."

His group consensus, supported by the International Society on Thrombosis and Haemostasis and four other professional societies, recommended standard-dose prophylactic anticoagulation in most cases, despite noting a lack of data. The World Health Organization and NIH guidelines also suggest only using a higher-dose anticoagulant if there is a strong suspicion of thrombosis or in the context of a prospective study.

More than nine randomized controlled trials are underway to address questions of type and dose of antithrombotics for prophylaxis in COVID-19, Bikdeli noted.

The NIH has announced the ACTIV-4 set of adaptive platform clinical trials to evaluate safety and effectiveness of varying types of antithrombotics for adults diagnosed with COVID-19.

Well-designed studies that include enrollment of patients in areas with higher case loads should be able to deliver some answers in 2 to 3 months, Bikdeli predicted. "Because if you practice in the ICU, these questions come up for almost every single patient with COVID-19. We see abnormal coagulation parameters and we ask ourselves, 'Do we increase the dose, do we not increase the dose?'"

But with the real risk of clinically important, even fatal, bleeding(We should have had research decades ago that would instantly identify patients at risk for this bleeding. ), "it's not really something that you can do just by clinical gestalt," he said. "Once we have the data, yes, clinical experience would be important to make patient-by-patient decisions. But without that prospective, ideally randomized, data, we're just going blindly."

Last Updated August 05, 2020

Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

Primary Source

medRxiv

Source Reference: Motta JK, et al "Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19" medRxiv 2020; DOI: 10.1101/2020.07.20.20147769.

Secondary Source

MedPage Today

Source Reference: Phend C "Full-Dose Clot Prophylaxis for COVID-19 Tied to Mortality" 2020.

Aspirin for primary atherosclerotic cardiovascular disease prevention as baseline risk increases: A meta-regression analysis

Two problems with this:

1.  WHO reclassified stroke in 2006, now a neurological disease not cardiovascular disease?

2. We need to come up with an exact test that will identify those at bleeding risk instead of these blanket warnings. This worked but for the bleeding risk.

Aspirin for primary atherosclerotic cardiovascular disease prevention as baseline risk increases: A meta-regression analysis

Nudy M, Cooper J, Ghahramani M, et al

American Journal of Medicine|June 26, 2020

Whether aspirin is more efficacious for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) as the baseline risk rises, was investigated via this meta-regression analysis. Researchers analyzed randomized controlled trials (RCTs) comparing aspirin with control for primary prevention as well as assessed ASCVD (composite of myocardial infarction and ischemic stroke) and major bleeding. Overall 12 RCTs with 963,829 patient-years of follow-up were found. Findings revealed that a decrease in ASCVD was achieved by using aspirin for primary prevention(So success?); however, its clinical significance is unlikely in view of the increase in bleeding. No increase in the treatment effect of aspirin was evident as ASCVD risk increased, as many hypothesize(You just contradicted your statement above). There is no hint from these findings that use of aspirin for higher-risk primary prevention patients is beneficial.

Read the full article on American Journal of Medicine.

Aspirin and fracture risk: a systematic review and exploratory meta-analysis of observational studies

So ask your doctor if this is the 81 or 325 dosage. Or is your doctor worried about the gastrointestinal bleeding risk?  And thus doesn't recommend aspirin at all? Listen to your doctor, not me, but ask plenty of questions.

In 2014, the FDA reversed its stance on daily low-dose aspirin as a
primary source of heart disease prevention, citing clearly established
side effects such as brain and stomach bleeding, as well as a lack of
clear benefit for patients who have never experienced a heart attack,
stroke or cardiovascular disease.

Aspirin and fracture risk: a systematic review and exploratory meta-analysis of observational studies

1. A L Barker1,2,
2. Sze-Ee Soh1,3,
3. Kerrie M Sanders4,5,
4. Julie Pasco6,
5. Sundeep Khosla7,
6. Peter R Ebeling8,
7. Stephanie A Ward1,
8. Geeske Peeters9,
9. Jason Talevski4,5,
10. Robert G Cumming10,
11. Ego Seeman11,12,
12. John J McNeil1

Abstract

Objectives This review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin.

Methods We conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged ≥18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models.

Results Twelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I²=71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI −0.02 to 0.07; I²=0%; three studies; n=9686) and men (SMD 0.06, 95% CI −0.02 to 0.13, I²=0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI −0.03 to 0.09; I²=34%; four studies; n=11 330) and men (SMD 0.08; 95% CI −0.01 to 0.18; one study; n=432).

Conclusions While the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Physicians: B.E.D. In Adults - B.E.D. Symptoms In Adults

B

The efficacy and safety of aspirin as the primary prevention of cardiovascular disease: An updated meta-analysis

So ask your doctor what factors cause major bleeding or gastrointestinal bleeding from use of aspirin.

The efficacy and safety of aspirin as the primary prevention of cardiovascular disease: An updated meta-analysis

Therapeutics and Clinical Risk Management — Xie W, et al. | September 26, 2019

Researchers performed an updated meta-analysis of 14 studies to assess the efficacy and safety of aspirin for the primary prevention of cardiovascular disease. Eligible studies included randomized, controlled trials comparing aspirin with placebo or no treatment that were published up to November 1, 2018. The primary efficacy endpoint was all-cause death, with secondary endpoints including cardiovascular death, myocardial infarction, and stroke. Major bleeding, gastrointestinal bleeding, and hemorrhagic stroke comprised safety endpoints. Compared with placebo or no treatment, aspirin was linked to a lower risk of myocardial infarction. Compared with control groups, however, aspirin was no linked to a lower risk of all-cause mortality or cardiovascular mortality. With respect to safety, aspirin was associated with a higher risk of major bleeding, gastrointestinal bleeding, and hemorrhagic stroke. In addition, patients’ clinical characteristics did not greatly influence the treatment affect.

Read the full article on Therapeutics and Clinical Risk Management

Is It Time to Start Stopping Aspirin for Stroke Prevention in Afib?

For discussion with your doctor. Ask how they determine bleeding risk before you actually start aspirin.

Is It Time to Start Stopping Aspirin for Stroke Prevention in Afib?

The Skeptical Cardiologist questions a die-hard habit

• by Anthony Pearson, MD July 17, 2019

Old habits die hard in medicine. For decades, the Skeptical Cardiologist and his cardiology brethren and sistren have prescribed aspirin to prevent stroke in patients with atrial fibrillation.
For those patients with atrial fibrillation (Afib, AF) who were considered low risk, it was felt that aspirin provided some benefit in preventing the clots that fly out of the heart (and land in arteries elsewhere in the body) at an acceptably low risk of bleeding. For higher risk patients, more powerful and effective agents -- oral anticoagulants -- are usually recommended.
The 2014 American guidelines on AF gave a IIB recommendation to aspirin: "For patients with nonvalvular AF and a CHA₂DS₂-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant (OAC) or aspirin may be considered (Level of Evidence: C)." IIB is not a ringing endorsement, having been described as "this is our suggestion, but you may want to think about it."
However, in the last 5 years the significant bleeding risks associated with taking low dose aspirin have become more widely appreciated.
Thus, in the 2016 European guidelines on the management of AF, the authors state that "the evidence supporting antiplatelet monotherapy [e.g., aspirin or clopidogrel] for stroke prevention in AF is very limited" and the bleeding rate is "similar" to OAC. A summary in the European Heart Journal said:
"Aspirin and other antiplatelets have no role in stroke prevention (III A). The combination of anticoagulation with antiplatelets increases bleeding risk and is only justified in selected patients for a short period of time; for example, in patients with an acute coronary syndrome or stent, balancing the risk of bleeding, stroke and myocardial ischaemia (IIa B/C)."
The European guidelines strongly recommend anticoagulation for males with a CHA₂DS₂-VASc score ≥2 and females ≥3. While the recommendation is also to consider anticoagulation in males with scores of 1 and females with scores of 2, no antithrombotic therapy of any kind should be prescribed in patients with scores below that.
The guidelines add: "Antiplatelet therapy increases bleeding risk, especially dual antiplatelet therapy (2.0% vs. 1.3% with antiplatelet monotherapy; P<0.001), with bleeding rates that are similar to those on OAC. Thus, antiplatelet therapy cannot be recommended for stroke prevention in AF patients."
While the 2019 focused update on AF from America said nothing about aspirin monotherapy for AF, it's not just European experts who feel this way. At a 2016 Cardiovascular CME conference, American experts in the field were unanimous in their condemnation of aspirin use for low-risk patients, as reported by MDedge:
"The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current US guidelines. I don't think aspirin should be in there and I don't think it will be there in the next guidelines. The role of aspirin will fall away," said Bernard J. Gersh, MB, ChB, DPhil, Professor of Medicine at the Mayo Clinic in Rochester, Minnesota. "It's not that aspirin is less effective than the oral anticoagulants, it's that there's no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation."
"The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly," said N.A. Mark Estes III, MD, Professor of Medicine and Director of the New England Cardiac Arrhythmia Center at Tufts University in Boston, and a past president of the Heart Rhythm Society.
"... I would just take it off of your clinical armamentarium because the best available data indicate that it doesn't prevent strokes. I'm certainly not using it in my patients. Increasingly in my patients with a CHA2DS2-VASc of 1, I'm discussing the risks and benefits of a novel oral anticoagulant," said Dr. Estes.
Those are amazingly definitive statements. But as I've learned, we can't just accept what the "experts" and the guidelines tell us -- we have to look at the original studies informing these decisions.
In 1991, the seminal study proving the benefits of warfarin in preventing stroke, the Stroke Prevention in Atrial Fibrillation (SPAF) trial, was published.
It compared warfarin (measured by prothrombin time, or INR ratio) to placebo as well as aspirin (325 mg) to placebo in preventing stroke in AF patients. Warfarin reduced stroke by 67% and aspirin by 42%. The risk of significant bleeding was similar at around 1.5% per year for all three arms.
Based on this and other AF trials (AFASAK, CAFA, SPINAF, EAFT, et al.), my message when I gave talks or taught cardiology fellows in the 1990s (similar to this presentation) emphasized the superior benefits of warfarin compared to aspirin (especially when monitored by INR in a 2.0 to 3.0 range) in higher-risk AF patients. Overall it was felt that aspirin (dosing varying from 100 to 325 mg) reduced stroke/embolism by 20% to 30% compared to placebo and would offer benefit to those patients at low risk or who could not tolerate warfarin.
Based on the 2014 American guidelines (and a focused update in 2019 that did not address this issue), I had not been actively taking my low-risk patients off baby aspirin.
I was prompted to re-research this question and write this post because a 58 year old woman with paroxysmal AF and hypertension called the office recently asking if I wanted her to take a baby aspirin daily. She has a CHA₂DS₂-VASc score of 2 (woman and hypertension) and falls into the category where we should have an in-depth conversation about the risks and benefits of anticoagulant therapy.
I have that discussion with her each visit, and thus far we've decided to hold off on starting an anticoagulant drug like apixaban (Eliquis). She has promised to record her ECG daily (using her Kardia Mobile ECG device) and report any onset of AF. If AF recurs, we will have another discussion about the anticoagulant.
I spent several hours pouring over the original studies and more recent studies, reviews, and meta-analyses and reached the following conclusions:
With the advent of the newer oral anticoagulants (NOACs) in the last decade that offer better stroke reduction and less bleeding than warfarin, patient-physician discussions should be about taking a NOAC or not. Aspirin should not be considered as a lower-risk/effective alternative as its benefits are minimal and bleeding risks similar to NOACs.
I told my patient no on the daily baby aspirin, and from now on I will recommend stopping aspirin (assuming no other reason to be on it) to all my low-risk AF patients.
Anthony Pearson, MD, is a private practice noninvasive cardiologist and medical director of echocardiography at St. Luke's Hospital in St. Louis. He blogs on nutrition, cardiac testing, quackery, and other things worthy of skepticism at The Skeptical Cardiologist, where a version of this post first appeared.