Collaboration on the optimal timing of anticoagulation after ischaemic stroke and atrial fibrillation: a systematic review and prospective individual participant data meta-analysis of randomised controlled trials (CATALYST)

 Didn't this earlier research prompt your competent? doctor and hospital to have this done already?

anticoagulation (24 posts to November 2014)

Do you prefer your doctor and hospital incompetence NOT KNOWING? OR NOT DOING? And they've been completely incompetent for almost two years already. Why haven't they been fired yet!

The latest here:

Collaboration on the optimal timing of anticoagulation after ischaemic stroke and atrial fibrillation: a systematic review and prospective individual participant data meta-analysis of randomised controlled trials (CATALYST)

Hakim-Moulay Dehbi, PhDa,† ∙ Prof Urs Fischer, MD MScb,† ∙ Signild Åsberg, MD PhDc,† ∙ Truman J Milling, MDd,† ∙ Stefanie Abend, BScb ∙ Norin Ahmed, MSca ∙ et al. Show more

Cover Image - The Lancet, Volume 406, Issue 10498

Background

The optimal timing of oral anticoagulation for prevention of early ischaemic stroke recurrence in people with acute ischaemic stroke and atrial fibrillation remains uncertain. We aimed to estimate the effects of starting a direct oral anticoagulant (DOAC) early (≤4 days) versus later (≥5 days) after onset of ischaemic stroke.

Methods

For this systematic review and meta-analysis we searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase for randomised controlled trials published from inception until March 16, 2025. We included clinical trials if they were pre-registered, randomised, investigated clinical outcomes, and included participants with acute ischaemic stroke and atrial fibrillation who were assigned to either early or later initiation (≤4 days vs ≥5 days) of a DOAC in approved doses. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days of randomisation. Secondary outcomes included components of the primary composite within 30 days and 90 days. We did a one-stage individual patient data meta-analysis with the use of a generalised linear mixed-effects model, accounting for between-trial differences, to generate treatment effects, which are presented as odds ratios (ORs) and 95% CIs. This study is registered with PROSPERO, CRD42024522634.

Findings

We identified four eligible trials: TIMING (NCT02961348), ELAN (NCT03148457), OPTIMAS (NCT03759938), and START (NCT03021928). After excluding participants who opted out of data sharing or were not randomly assigned to DOAC initiation within 4 days or at day 5 or later, we included 5441 participants (mean age 77·7 years [SD 10·0], 2472 [45·4%] women, median National Institutes of Health Stroke Scale 5 [IQR 3–10]) in the individual patient data meta-analysis. We obtained primary outcome data for 5429 participants. The primary outcome occurred in 57 (2·1%) of 2683 participants who started DOAC early versus 83 (3·0%) of 2746 participants who started later (OR 0·70, 95% CI 0·50–0·98, p=0·039). Early DOAC reduced the risk of recurrent ischaemic stroke (45 [1·7%] of 2683 vs 70 [2·6%] of 2746, OR 0·66, 0·45–0·96, p=0·029). There was no evidence of an increase in symptomatic intracerebral haemorrhage with early DOAC initiation (10 [0·4%] of 2683 vs 10 [0·4%] of 2746, OR 1·02, 0·43–2·46, p=0·96).

Interpretation

For people with acute ischaemic stroke and atrial fibrillation, early DOAC initiation (within 4 days) reduced the risk of the composite outcome of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days. These findings support early DOAC initiation in clinical practice.

Funding

The CATALYST collaboration was facilitated by a British Heart Foundation grant for OPTIMAS (grant reference number CS/17/6/33361), with support from researchers at the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and a Swiss National Science Foundation grant for ELAN (32003B_197009; 32003B_169975).

Introduction

Atrial fibrillation causes about 20–30% of ischaemic strokes, which are generally more disabling than strokes associated with other causes.1 Direct oral anticoagulants (DOACs) are highly effective in long-term secondary prevention after ischaemic stroke associated with atrial fibrillation and are associated with about half the risk of intracranial haemorrhage compared with vitamin K antagonists.2 However, the optimal timing of initiation of anticoagulation after acute ischaemic stroke in atrial fibrillation is a persisting clinical dilemma, since the pivotal DOAC trials excluded participants with recent acute ischaemic stroke (ie, within 7–30 days). Although early DOAC might reduce the risk of early ischaemic stroke recurrence due to cardiac embolism, early use of DOACs must be balanced against concerns regarding haemorrhagic transformation of the acute infarct which could, if severe, worsen clinical outcomes. A recent aggregate data meta-analysis3 including observational and randomised studies suggested that early DOAC treatment might be safe, but these data are limited by potential biases and confounding.

Research in context

Evidence before this study

Pivotal randomised controlled trials showed that direct oral anticoagulants (DOACs) are highly effective for the prevention of ischaemic stroke in people with atrial fibrillation, but did not include participants soon after acute ischaemic stroke (within about 1–2 weeks). Early DOAC use might reduce the risk of early ischaemic stroke recurrence due to cardiac embolism but might also increase haemorrhagic transformation of the acute infarct that could, if severe, worsen clinical outcomes. We searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase on May 16, 2024 (with an additional updated search on March 16, 2025), for randomised controlled trials comparing early versus delayed start of DOAC. The main search terms were “acute ischaemic stroke” AND “atrial fibrillation” AND “anticoagulants” AND “timing” AND “randomised”. We identified four published trials (TIMING, ELAN, OPTIMAS, and START). The risk of bias, assessed according to the revised Cochrane risk-of-bias tool for randomised trials, was low. None of the four trials alone provided unequivocal evidence that early DOAC treatment was preferable to delayed initiation.

Added value of this study

We performed an individual patient data meta-analysis including 5441 participants from TIMING, ELAN, OPTIMAS, and START (mean age 77·7 years [SD 10·0], 2472 [45·4%] women, median National Institutes of Health Stroke Scale score at admission 5 [IQR 3–10]) to investigate the effects of early DOAC initiation within 4 days versus later DOAC initiation (at day 5 or later). Our results showed a reduction of the primary outcome, a composite of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days. The primary outcome occurred in 57 (2·1%) of 2683 participants who started a DOAC early versus 83 (3·0%) of 2746 in the delayed DOAC group. The benefits were consistent across key prespecified subgroups including clinical stroke severity, reperfusion treatment, and previous use of oral anticoagulants.

Implications of all the available evidence

Our findings suggest that clinicians should initiate DOAC treatment within 4 days and do not support the practice of delaying DOAC initiation after acute ischaemic stroke with atrial fibrillation. Future CATALYST subgroup analyses will further explore the risks and benefits of early initiation of DOACs.

Direct oral anticoagulants increase bleeding risk after intracerebral hemorrhage in patients with atrial fibrillation

 Hope your stroke medical 'professionals' read AND IMPLEMENT RESEARCH!

Direct oral anticoagulants increase bleeding risk after intracerebral hemorrhage in patients with atrial fibrillation

1. Ischemic stroke occurred less often in patients with atrial fibrillation on DOACs compared to those on placebo.

2. Patients in the DOAC group reported an increased risk of intracerebral hemorrhage.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Patients with atrial fibrillation are often prescribed direct oral anticoagulants (DOACs) to reduce the risks of thromboembolism and stroke. However, the safety and efficacy of restarting anticoagulation after spontaneous intracerebral hemorrhage (ICH) remains uncertain. This randomized controlled trial aimed to determine whether DOACs could reduce the risk of ischemic stroke without significantly increasing the risk of recurrent ICH in this high-risk population. The primary outcome was first occurrence of ischemic stroke, while key secondary outcome was recurrence of ICH. According to study results, DOACs significantly lowered the risk of ischemic stroke compared to no anticoagulation; however, they were also associated with a higher risk of recurrent ICH. Although this study was well done, it was limited by a small sample size, which may affect the generalizability of its findings.

Click to read the study in The Lancet

Relevant Reading: Early versus Later Anticoagulation for Stroke with Atrial Fibrillation

RELATED REPORTS

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2 Minute Medicine Rewind April 21, 2025

In-depth [randomized controlled trial]: Between May 31, 2019, and Nov 30, 2023, 327 patients were assessed for eligibility across 75 hospitals in 6 European countries. Included were patients ≥ 18 years with spontaneous ICH, a clinical diagnosis of atrial fibrillation, and a modified Rankin Scale score ≤ 4. Altogether, 319 patients (158 in DOAC group and 161 in no anticoagulant group) were included in the final analysis. The primary outcome of ischemic stroke occurred significantly less often in the DOAC group (hazard ratio [HR] 0.05, 95% confidence interval [CI] 0.01-0.36, log-rank p<0.0001). The secondary outcome of recurrent ICH occurred more frequently in the DOAC group (event rate 5.00 per 100 patient-years in DOAC vs. 0.82 per 100 patient-years in placebo). Findings from this study suggest that while DOACs reduce the risk of ischemic stroke in patients with atrial fibrillation, they increase bleeding.

Image: PD

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Brain Bleed Survivors Walk a Razor-Thin Line Taking DOACs

 What does your competent? say about this conundrum? Does s/he explain both sides clearly?

Brain Bleed Survivors Walk a Razor-Thin Line Taking DOACs

      In PRESTIGE-AF, robust ischemic protection offset by recurrent ICHs

by Nicole Lou, Senior Staff Writer, MedPage Today February 9, 2025

LOS ANGELES -- In the PRESTIGE-AF trial, survivors of intracerebral hemorrhage (ICH) had good protection against future ischemic events using direct oral anticoagulants (DOACs) -- though, as feared, bleeding side effects reared their ugly heads.

Study participants, people weeks or months out from their index spontaneous ICH who also had atrial fibrillation (Afib), had a major reduction in their risk of a first ischemic stroke (adjusted HR 0.05, 95% CI 0.01-0.38) over a mean follow-up of 1.43 years if they had been randomized to DOAC therapy instead of no anticoagulation (OAC) in the trial.

Altogether, ischemic strokes occurred at a low 0.83 per 100 patient-years with DOACs versus 8.60 per 100 patient-years with no OAC. The number needed to treat (to prevent one ischemic stroke per year) was just 13, reported Roland Veltkamp, MD, of Imperial College London, at the International Stroke Conference.

The bad news was that there was also a major risk of recurrent ICH associated with DOAC therapy (adjusted HR 11.2, 95% CI 2.01-62.86). The incidence of all ICH events reached 5.00 per 100 patient-years versus 0.82 per 100 patient-years, between DOAC and controls, and the number needed to harm (to cause one more ICH per year) was 24.

Calculations of net clinical benefit ultimately did not tilt towards either study group in the 319-person trial.

Thus, nearly 6 years since the start of the study, it remains a conundrum how ICH survivors with Afib are supposed to balance their opposing risks of recurrent bleeding and ischemic events. Looking forward, the data from the ongoing phase III trials ENRICH-AF and ASPIREopens in a new tab or window may clarify the risk-benefit profile of DOACs in this setting.

For one, the sheer amount of bleeding that occurred in PRESTIGE-AF came as a surprise to Joao Gomes, MD, of Cleveland Clinic.

"Observational data and subsequent meta-analyses had suggested no increase in recurrent ICH risk in patients treated with vitamin K antagonist agents. Similarly, preliminary pilot data on DOACs for ischemic stroke prevention in Afib patients following ICH had showed encouraging safety trends. It was a bit surprising that the risk of subsequent ICH was as high as it was reported in PRESTIGE-AF. Similarly, one would have also expected a higher recurrent ICH risk early on that hopefully stabilized over time, but that did not seem to be the case," Gomes told MedPage Today in an email.

Meanwhile, there is also interest in alternative therapies such as left atrial appendage (LAA) closure -- which had been among the exclusion criteria of PRESTIGE-AF. Veltkamp said the long-term goal is to find imaging and other markers that help personalize the care of each ICH survivor, as some may be better suited to DOACs, and some to other interventions.

"It is becoming increasingly clear that a more individualized approach (i.e., biomarkers that can more accurately predict recurrent ICH risk) is needed for optimal risk stratification of patients facing this conundrum," agreed Gomes.

"Clinicians who treat stroke survivors face this challenging situation on a frequent basis, and thorough discussions with patients and their surrogates are required to properly inform them of potential risks and benefits of any approach, while assisting in the decision-making process and until more definitive data are available," he urged.

PRESTIGE-AF was a phase III open-label trial conducted in 63 European sites. Investigators recruited adults who were between 14 days and a year out from their index spontaneous ICH, were diagnosed with Afib, and had an indication for anticoagulation and no contraindication to therapy.

Participants were randomized 1:1 to a standard-dose DOAC or control without any OAC. The choice of the DOAC was left to each site. Ultimately, the study ended up with patients receiving mostly apixaban (53.8%), followed by dabigatran (20.9%) and edoxaban (18.4%).

The final 319-person cohort had a median age of 78-79 and was 35% women. Nearly all participants were white. The median CHA2DS2-VASc score was 4 and the HAS-BLED score a 3. It typically took people just under 50 days between index ICH and study enrollment. Median ICH volumes had been 4.2 mL and 3.2 mL between DOAC and control groups, respectively. The index ICH had been non-lobar in about 70% of cases, the rest lobar.

Outside the bleeding outcomes clearly favoring the control arm, secondary endpoints like mortality and major adverse cardiac events did not suggest that either strategy was better.

Veltkamp and colleagues acknowledged the limited generalizability of the trial beyond the largely white populations studied. The authors had also limited their pool to people with small index ICH volumes and no severe disability.

The PRESTIGE-AF group had started out expecting 654 participants; due to slow enrollment, the authors revised their power calculations later on, settling on a goal of 312 participants.

• 

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

Disclosures

PRESTIGE-AF was funded by a grant from the European Union's Horizon 2020 program.

Veltkamp disclosed personal advising to AstraZeneca and BMS-Pfizer; and research funding from Bayer, BMS-Pfizer, Boehringer Ingelheim, and Daiichi Sankyo.

Gomes had no disclosures.

Primary Source

International Stroke Conference

Source Reference: Veltkamp R "Effects of direct oral anticoagulants versus no anticoagulation in the prevention of stroke in intracerebral haemorrhage survivors with atrial fibrillation trial" ISC 2025.

Stroke Survivors With Afib Could Start DOACs Earlier

 Did your competent? doctor and hospital know about this research and create a protocol on it immediately? NO? So, you don't have a functioning stroke doctor or hospital, do you? 

Better not have a stroke and get transported to that hospital.

Stroke Survivors With Afib Could Start DOACs Earlier

Safety shown with no difference in recurrent strokes

by Nicole Lou, Senior Staff Writer, MedPage Today October 25, 2024

It was safe to start direct oral anticoagulant (DOAC) therapy without delay after acute ischemic stroke in people with atrial fibrillation (Afib), according to the OPTIMAS randomized trial.

Stroke survivors randomized to early or delayed DOAC initiation had the same 3.3% incidence of composite recurrent ischemic stroke, symptomatic intracranial hemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days (P=0.0003 for noninferiority), reported a group led by David Werring, PhD, of University College London in The Lancetopens in a new tab or window.

Additionally, there was a "very low" incidence of symptomatic intracranial hemorrhage either way (0.6% early vs 0.7% delayed, P=0.78) -- and the risk did not vary by stroke severity.

Consistent with other trials of early DOAC initiation, Werring's group concluded OPTIMAS thus provides "reassurance for the safety of early anticoagulation with a DOAC and do not support the common current guideline-supported practice of delaying oral anticoagulation after acute ischemic stroke with atrial fibrillation for up to 14 days after moderate-to-severe acute stroke."

"Early DOAC initiation also has the potential practical advantage of improving the proportion of patients who start secondary prevention treatment before hospital discharge, although this is not shown by our data and should be investigated in further studies," study authors added.

In the absence of high-quality evidence, the current recommendations to wait on DOAC initiation stem from concerns about the risk of early intracranial hemorrhage in this setting. Yet evidence has been accruing, in recent trials like ELANopens in a new tab or window, that an earlier start to anticoagulation is safe and may in fact improve outcomes in people with Afib after a stroke.

OPTIMAS builds on this literature despite not finding evidence of superiority with early DOAC initiation (P=0.96 for superiority). The finding of noninferiority was nevertheless unchanged when the authors accounted for the competing risk of mortality (8.8% for early initiation vs 8.9% for delayed initiation).

Notably, unlike ELAN, OPTIMAS investigators considered early DOAC initiation to be within 4 days of stroke onset (vs 48 hours) and late initiation to be within 7-14 days (vs day 6-7).

Werring's group also highlighted the relative broadness of the OPTIMAS population as it included people with severe stroke (for a trial-wide median NIH Stroke Scale score of 5) and those already taking an anticoagulant at the time of their stroke (32.2%).

The trial is ongoing, the authors noting that they are planning to conduct additional brain imaging analyses to see if there are any variables (e.g., hemorrhagic transformation, infarct volume, cerebral small vessel disease markers) that may alter the timing of DOAC therapy after ischemic stroke.

OPTIMAS was a multicenter open-label trial conducted at 100 U.K. hospitals from 2019 to 2024.

Participants were survivors of acute ischemic strokes likely related to their Afib. In the hospital stroke unit, they were randomized 1:1 to early or later DOAC initiation. Patients were not eligible if they had a coagulopathy or a high bleeding risk.

Ultimately, there were 3,621 patients (mean age 78.5 years, 45.3% women, 93.7% white) in the modified intention-to-treat analysis. Baseline characteristics were well balanced between groups, according to Werring and colleagues.

Patients had had their strokes treated with IV thrombolysis in 22.0% of cases, and endovascular therapy in 7.3%. After the stroke, 83.8% were put on antiplatelet therapy.

The DOAC initiated for the study was most commonly apixaban (Eliquis; 62.1%), followed by edoxaban (Savaysa; 28.9%).

The early DOAC group initiated on average 3.1 days after stroke onset; the later group initiated at 8.3 days.

Werring's team acknowledged that one of the trial's limitations was the lack of evaluation of DOAC initiation in the 4-7 days after stroke.

There were also few OPTIMAS participants with very severe strokes who actually made it to the trial, while the group of patients with parenchymal hematoma type 2 were excluded outright.

• 

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

Disclosures

OPTIMAS was funded by the British Heart Foundation.

Werring reported consulting fees from Novo Nordisk, the National Institute for Health and Clinical Excellence, and Alnylam; payments or speaker honoraria from Novo Nordisk, Bayer, and AstraZeneca/Alexion; participation on a data safety monitoring board for the OXHARP trial, participation as Steering Committee Chair for the MACE-ICH and PLINTH trials; serving as president of the British and Irish Association of Stroke Physicians; and holding a National Institute for Health and Care Research Senior Investigator Award.

Co-authors reported multiple relationships with industry and other organizations.

Primary Source

The Lancet

Source Reference: opens in a new tab or windowWerring DJ, et al "Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial" Lancet 2024; DOI: 10.1016/S0140-6736(24)02197-4.

Higher efficacy of intravenous thrombolysis in patients with acute ischemic stroke taking direct oral anticoagulants—A new relevant hypothesis

 I have no clue, so ask your competent? doctor what changes to the initial stroke protocol this will cause. 

Do you prefer your  doctor and hospital  incompetence NOT KNOWING? OR NOT DOING?

Higher efficacy of intravenous thrombolysis in patients with acute ischemic stroke taking direct oral anticoagulants—A new relevant hypothesis

Senta Frol^1,2*Janja Pretnar Oblak^1,2Pawel Kermer^3,4George Ntaios⁵Panagiotis Papanagiotou^6,7Mišo Šabovič^2,8

• ¹Department of Vascular Neurology, University Medical Center Ljubljana, Ljubljana, Slovenia
• ²Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
• ³Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Friesland Kliniken GmbH, Sande, Germany
• ⁴University Medical Center Göttingen, Göttingen, Germany
• ⁵Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
• ⁶Clinic of Diagnostic and Interventional Neuroradiology, Klinikum Bremen Mitte, Bremen, Germany
• ⁷Department of Radiology, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
• ⁸Department of Vascular Disorders, University Medical Center Ljubljana, Ljubljana, Slovenia

Introduction

Direct oral anticoagulants (DOACs) have been established as first-line therapy for stroke prevention in patients with non-valvular atrial fibrillation due to their high safety and efficacy, as demonstrated in large randomized controlled trials (RCTs) (1–4) and real-world data. Despite their efficacy, about 1%−2% of DOAC-treated patients suffer from acute ischemic stroke (AIS) (1–4). At the same time, intravenous thrombolysis (IVT) is recommended as first-line therapy for AIS patients (5, 6). Currently, alteplase is the preferred thrombolytic agent, while tenecteplase, which is more fibrin-specific and has a longer half-life, has recently been approved for IVT in AIS in Europe (7). However, most international guidelines advise against IVT in DOAC-treated patients who have ingested their medication within 48 h prior to AIS onset, except for dabigatran-treated patients reversed by idarucizumab (5, 8).

Ongoing debates regarding IVT safety in patients on DOACs speculate on possible pathophysiological explanations. It was hypothesized that both direct and indirect thrombin inhibition might reduce disruptions to the blood-brain barrier, thereby lowering the risk of hemorrhage (9, 10). Equally important is the high efficacy of IVT in DOAC-treated patients. Recently, no safety concerns regarding IVT were reported while patients receiving IVT were more likely to have good functional outcomes (11, 12).

In this context, this opinion article discusses about the potentially higher efficacy of IVT in patients on DOACs, a topic which warrants more in-depth exploration, such as enhanced fibrinolytic activity.

More at link.

DOACs Safe to Start Soon After Acute Ischemic Stroke

 Safety and possibly improved outcomes is NOT GOOD ENOUGH!. Why didn't you create robust research that determined efficacy? Your mentors and senior researchers incompetently didn't demand that? Survivors would like an EXACT PROTOCOL that delivers results. This didn't do that.

DOACs Safe to Start Soon After Acute Ischemic Stroke

Trial supports starting within 48 hours for many patients

by Crystal Phend, Contributing Editor, MedPage Today May 24, 2023

An earlier start to anticoagulation after an acute ischemic stroke for patients found to have atrial fibrillation appeared safe and possibly improved outcomes, according to the randomized ELAN trial.

Starting a direct oral anticoagulant (DOAC) within 48 hours for mild or moderate stroke or on day 6 or 7 in those with major stroke resulted in a 2.9% composite rate of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days.

That rate was 4.1% more typical strategy of initiation at day 3 or 4 after minor stroke, day 6 or 7 after moderate stroke, and day 12-14 after major stroke, researchers led by Urs Fischer, MD, of University Hospital Basel in Switzerland, reported in the New England Journal of Medicineopens in a new tab or window. The trial was also presented at the European Stroke Organization Conference in Munich, Germany.

While the trial had no formal hypothesis testing for superiority or even noninferiority, the 95% confidence interval for a difference between groups was consistent with anywhere from a 30-day risk reduction of 2.84 percentage points to an increase of about 0.5 percentage points with early anticoagulation.

"Early treatment initiation can therefore be supported if indicated or if desired,(Survivors would prefer not to have weasel words in their interventions!)" the researchers concluded. "The rates of the outcomes increased only slightly more at 90 days than at 30 days, findings that suggest there was not an excessive risk associated with early anticoagulation through that period."

Current clinical practice is to delay the initiation of anticoagulation after ischemic stroke, with the American Heart Association–American Stroke Association calling for waiting more than 14 days if there is a high risk of hemorrhagic transformation or starting anywhere from day 2 to day 14 if that risk is low.

"We're always trying to prevent recurrent stroke, but we don't want to cause hemorrhagic transformation," commented Geoffrey Barnes, MD, of the University of Michigan Frankel Cardiovascular Center in Ann Arbor. "There was a concern that with the direct oral anticoagulants, becoming essentially fully anticoagulated within just a couple of hours, there could be that risk of causing hemorrhagic transformation shortly after an ischemic stroke."

Along with the somewhat similarly designed but smaller TIMINGopens in a new tab or window trial, the findings "really provide us reassurance that the direct oral anticoagulants are not significantly increasing the risk of hemorrhagic transformation and may even be leading to fewer recurrent strokes," said Barnes, who was not involved in either trial.

The 30-day recurrent ischemic stroke rate was 1.4% with early treatment compared with 2.5% in the later-treatment group and 1.9% versus 3.1% at 90 days, which was not statistically significant in either case (OR 0.57, 95% CI 0.29-1.07, and 0.60, 95% CI 0.33-1.06).

"For everyday clinicians, this looks pretty similar to other randomized trials," said Barnes, pointing to the stroke risk curves that "clearly are trending towards favoring early treatment is better."

With meta-analysis potentially providing the odds ratios and hazard ratios for the primary endpoint that people are used to seeing, Barnes predicted that the "clear consistency" would be persuasive to guidelines committees too.

Perhaps most reassuring, though, according to Barnes, were the "very low" symptomatic intracranial hemorrhage rates of just 0.2% in both groups by 30 days.

"That goes along with everything seen from initial phase III of the direct oral anticoagulants to many of the real-world data studies we've seen, just showing that these drugs are remarkably safe when it comes to the risk of intracranial hemorrhage," he said. "So I was very much reassured by those data that we saw in a group of patients that are, I would think, very high risk."

The trial randomized 2,013 acute ischemic stroke patients (median age 77, 45% female) at 103 sites in 15 countries to open-label treatment with a DOAC in the two time frames. Of them, 37% had minor stroke (≤1.5 cm), 40% had moderate stroke (an infarct in the distribution of a cortical superficial branch of the middle, anterior, or posterior cerebral artery), and 23% had major stroke (≤1.5 cm in the distribution of these arteries, the brain stem, or cerebellum).

Stroke magnitude was determined by the site investigators on the basis of a standardized visual rating scheme for magnetic resonance imaging or computed tomography imaging performed before randomization. Median National Institutes of Health Stroke Scale (NIHSS) score was 5 at admission and 3 at randomization.

Study limitations included the exclusion of patients already receiving therapeutic anticoagulation at baseline and the low median NIHSS score at baseline. The trial also lacked demographic data for the participants; while they were enrolled from Europe, the Middle East, and Asia, the majority of the trial population came from predominantly white European areas.

The OPTIMASopens in a new tab or window -- Optimal Timing of Anticoagulation after Acute Ischaemic Stroke -- trial is ongoing in in the United Kingdom to add to the evidence.

• 

  Crystal Phend is a contributing editor at MedPage Today. Follow

Disclosures

The trial was supported by grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the Stroke Association in the United Kingdom, and the Intramural Research Fund for Cardiovascular Diseases of Japan's National Cerebral and Cardiovascular Center.

Fischer reported relationships with Alexion, Biogen, Boehringer Ingelheim, Medtronic, Penumbra, Phenox, Rapid Medical, and Stryker; other co-authors also reported various disclosures.

Barnes disclosed relationships with Janssen, Pfizer, Bristol Myers Squibb, and Bayer.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowFischer U, et al "Early vs late anticoagulation in stroke patients with atrial fibrillation" N Engl J Med 2023; DOI: 10.1056/NEJMoa2303048.

Encouraging Data for Stroke Lytics in DOAC Users

Do you really think your hospital reads and implements research?

Encouraging Data for Stroke Lytics in DOAC Users

Observational cohort shows "counterintuitive" finding on sICH risk

by Nicole Lou, Senior Staff Writer, MedPage Today January 3, 2023

Thrombolytic use in select stroke patients with recent direct oral anticoagulant (DOAC) ingestion did not raise the risk of the most feared bleeding complication, according to the largest-yet observational dataset.

In fact, the 832 such patients receiving off-label IV thrombolysis within the standard time window for ischemic stroke actually experienced a lower incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours compared with controls without anticoagulant use in the prior 48 hours (2.5% vs 4.1%; adjusted OR 0.57, 95% CI 0.37-0.92), reported David Seiffge, MD, of Bern University Hospital in Switzerland, and colleagues.

This "counterintuitive" finding was consistent across the different selection strategies for IV thrombolysis -- DOAC-level measurements, DOAC reversal with idarucizumab (Praxbind), or neither. It also held up in people with very recent DOAC intake and persisted after accounting for mechanical thrombectomy, large vessel occlusion, and concomitant antiplatelet therapy, the investigators reported in JAMA Neurologyopens in a new tab or window.

"Given the established benefits of IV thrombolysis and the absence of any signal for harm in our study or in other clinical studies or preclinical investigations, future guideline updates need to reconsider recent DOAC ingestion as a contraindication to IV thrombolysis for acute ischemic stroke," they urged.

In theory, recent DOAC use -- taken for stroke prevention or a growing list of other indications -- might protect against sICH through mechanisms related to faster recanalization, smaller infarct volumes, and thrombin inhibition against sICH, Seiffge and colleagues suggested.

They reported that recent users of DOACs who received IV thrombolysis had first been given reversal agents in 30.3% of cases, had measurement of DOAC levels in 27.0%, and neither in 42.7%.

"Notwithstanding the small number of patients in each group, it is reassuring to see that rates of sICH were comparable among these selection strategies," commented Eva Mistry, MBBS, MSCI, a vascular neurologist at the University of Cincinnati.

"However, the study lacks data on recently emerging anti Xa measurement-based selection for thrombolysis. Anti-Xa level measurement is potentially more widely available compared to DOAC level measurement and correlates well with drug levels," she wrote in an accompanying editorialopens in a new tab or window.

The retrospective cohort study spanned 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand and included consecutive adult patients with ischemic stroke from 2008 to 2021. Thrombolysis consisted of alteplase (Activase) in the bulk of cases, with few individuals receiving tenecteplase (TNKase).

Included were 832 patients who had used a DOAC within 48 hours of thrombolysis -- a fairly large addition to the limited literature -- compared against 32,375 controls without recent anticoagulant use. Notably, the control population was treated across a somewhat different time frame than the thrombolysis patients and came only from European centers, some of which did not contribute to the DOAC arm of the study, Mistry cautioned.

The overall study cohort had a median age of 73 years and 43.5% women. Median NIH Stroke Scale score was 9, and time from stroke onset to thrombolysis was 138 minutes.

Compared with controls, patients with recent ingestion of DOACs were older and had a higher prevalence of hypertension but less smoking, had greater pre-stroke disability and more severe strokes, waited longer for treatment, and were more likely to have a large vessel occlusion.

The DOACs that had most commonly been ingested prior to stroke were dabigatran (Pradaxa, 41%), rivaroxaban (Xarelto, 31%), and apixaban (Eliquis, 20%).

The study's nonrandomized design left room for potential confounding and bias, the authors acknowledged.

"Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population," according to Mistry.

However, Seiffge and colleagues said a randomized trial designed to assess the safety of thrombolytics in patients with recent ingestion of DOACs is unlikely to be financed or completed in a timely fashion.

• 

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

Disclosures

The study was supported by a grant from the Bangerter-Rhyner Foundation

Seiffge reported personal fees from Bayer, Alexion, and VarmX.

Mistry disclosed receiving grant funding from the National Institute of Neurological Disorders and Stroke and consulting for RAPID AI.

Primary Source

JAMA Neurology

Source Reference: opens in a new tab or windowMeinel TR, et al "Intravenous thrombolysis in patients with ischemic stroke and recent ingestion of direct oral anticoagulants" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.4782.

Secondary Source

JAMA Neurology

Source Reference: opens in a new tab or windowMistry EA "Building evidence on safety of thrombolysis for patients undergoing direct oral anticoagulant treatment" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.4765.

Haphazard Aspirin Add-On: Not a Great Risk-Reward Tradeoff for DOAC Users

The real solution is to create a test that identifies EXACTLY which persons are susceptible to bleeding from aspirin rather than these blanket prohibitions. In business you'd be fired for not going directly to and solving the root cause.  But I'm not medically trained so don't listen to me.

Haphazard Aspirin Add-On: Not a Great Risk-Reward Tradeoff for DOAC Users

Group suggests deprescribing aspirin with no clear indication

by Nicole Lou, Staff Writer, MedPage Today April 19, 2021

Direct oral anticoagulant (DOAC) users without a clear indication for aspirin were often prescribed combination therapy only to wind up with a higher risk of bleeding and no reduction in thrombotic events, an observational study showed.

People with atrial fibrillation (Afib) or venous thromboembolism (VTE) -- but no recent MI or history of heart valve replacement -- were treated with concomitant aspirin atop their DOAC in 33.8% of cases, making this a "common" phenomenon, according to Jordan Schaefer, MD, of the University of Michigan in Ann Arbor, and colleagues.

Comparison between 1,047 matched pairs revealed that combination and DOAC monotherapy groups differed in some key outcomes over a median 12 months of follow-up:

• All bleeding: 31.6 vs 26.0 per 100 patient-years (P=0.01)
• Nonmajor bleeding: 26.1 vs 21.7 per 100 person-years (P=0.02)
• Major bleeding: 4.95 vs 3.59 per 100 person-years (P=0.09)
• Thrombotic events: similar at 2.5 vs 2.3 per 100 patient-years (P=0.80)
• Hospitalizations: 9.1 vs 6.5 per 100 patient years (P=0.02)
• Mortality: 3.8 vs 3.4 per 100 patient-years (P=0.76)

"Ultimately, while emerging data seem to suggest that anticoagulant monotherapy alone may be sufficient for some patients, further confirmation of these findings is necessary," Schaefer's group wrote in JAMA Internal Medicine.

"Efforts should be made to help clinicians identify and deprescribe ASA [aspirin] for patients taking a DOAC without an indication for ASA," they maintained.

The group had previously shown excess bleeding with combination aspirin and warfarin therapy in patients lacking a clear indication for aspirin.

"It is important to acknowledge that there are numerous patient subgroups and clinical scenarios where the role of combination therapy compared with that of anticoagulant monotherapy has not been sufficiently studied," Schaefer's group noted, citing examples such as people with vascular stents, myeloproliferative neoplasms, poorly controlled vascular risk factors, and thrombophilias.

"In such scenarios, shared decision-making and individualized care should remain standard," they stated.

The study relied on the Michigan Anticoagulation Quality Improvement Initiative for registry data from four anticoagulation clinics in Michigan.

Participants were 3,280 adults with Afib or VTE without a clear indication for aspirin (51.0% men; mean age 68.2). All had started taking a DOAC -- namely apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Savaysa), or rivaroxaban (Xarelto) -- in 2015-2019.

Main study results were largely supported by sensitivity analyses such as those that excluded patients with any history of MI, coronary artery disease, or peripheral artery disease; or excluded those who started or stopped aspirin after study enrollment.

Even so, investigators cautioned that the observational nature of the study left room for unmeasured confounding and was unable to capture changes in aspirin use during follow-up. Moreover, the study may not be generalizable to geographic areas outside Michigan.

"Finally, the overall rates of thrombosis and many bleeding subtypes were low. Accordingly, this study is likely underpowered to make conclusions about thrombotic outcomes and outcomes of some bleeding subtypes," according to Schaefer and colleagues.

• 

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

Disclosures

The study was funded by Blue Cross Blue Shield of Michigan.

Schaefer disclosed no relevant relationships with industry. Co-authors disclosed multiple relevant relationships with industry.

Primary Source

JAMA Internal Medicine

Source Reference: Schaefer JK, et al "Adverse events associated with the addition of aspirin to direct oral anticoagulant therapy without a clear indication" JAMA Intern Med 2021; DOI: 10.1001/jamainternmed.2021.1197.

 

Holding tPA for All DOAC(direct oral anticoagulant) Users Not the Way to Go, Stroke Docs Say

So until this Thromboelastography test exists and is a well documented protocol you can wait 48 hours after your last DOAC injestion before you get tPA. Hope you don't mind killing off billions of neurons.  Just maybe you'll need to direct your doctor to use mechanical thrombectomy instead of waiting. Hope you are conscious enough to do that.  Of course the simplest solution would be for you to lie and say you haven't taken any DOACs recently so you could get tPA immediately. This means this test would need to be available in the ambulance so you can get your tPA shot in the ambulance, waiting till hospital kills off way too many neurons.

Holding tPA for All DOAC Users Not the Way to Go, Stroke Docs Say

Clinical conundrum could be solved by a point-of-care DOAC test

by Nicole Lou, Staff Writer, MedPage Today March 15, 2021

Current guidance on how to manage stroke patients on direct oral anticoagulant (DOAC) therapy isn't right, but there aren't the validated tools needed to do better either, lamented clinicians.

DOACs taken for stroke prevention may turn out to be the very reason for withholding treatment in acute stroke: guidelines from the American Heart Association and American Stroke Association have a class III recommendation against thrombolysis within 48 hours of last DOAC intake for fear of bleeding.

"We strongly disagree with this generalized recommendation," wrote a group led by David Seiffge, MD, of the University Hospital of Bern, Switzerland, in one of two viewpoint articles published online in JAMA Neurology.

"Available data show that carefully selected patients taking prior DOAC therapy have similar bleeding risks to patients not taking DOAC after IV thrombolysis," they argued.

Rather than categorically excluding DOAC users from recanalization therapies, stroke treatment could incorporate selection of patients for thrombolysis based on drug-specific assays (e.g., thromboelastography) and use of reversal agents before thrombolysis (e.g., idarucizumab [Praxbind] reversal of dabigatran [Pradaxa], andexanet alfa [Andexxa] reversal of factor Xa inhibitors) if necessary, Seiffge and colleagues suggested.

Thromboelastography shows promise for point-of-care testing, as it measures viscoelastic properties of clotting blood and correlates with serum DOAC levels. However, selection for thrombolysis using this method has yet to be reported, and it needs to be more broadly available in the first place.

"Why are anti-Xa activity assays not more available? A strong call for further validation and more availability of these tests should be a priority, rather than a recommendation to fly by the seat of our pants, so to speak, by giving a reversal agent and hoping for the best," wrote Alexandra Czap, MD, of the University of Texas Health Science Center, and James Grotta, MD, of Memorial Hermann Hospital-Texas Medical Center, both in Houston, in another JAMA Neurology viewpoint piece.

The strategy of anticoagulant reversal before IV thrombolysis also suffers from the lack of data beyond observational reports.

Reversal agents are not all equal, either, as andexanet alfa as compared with idarucizumab provides "much less reliable and durable reversal at a much higher cost for the most commonly used DOACs," according to Czap and Grotta.

"[H]aving a point-of-care test available in the prehospital setting or emergency department would make all the difference in being sure that the patient needs the reversal agent and it has been successful in reversing DOAC activity," the pair wrote.

Both published viewpoints alluded to the low likelihood of convincing randomized data coming out to assess DOAC reversal strategies before stroke thrombolysis.

Seiffge's group raised another clinical conundrum: whether to offer bridging thrombolysis before endovascular thrombectomy among DOAC users in acute ischemic stroke.

This decision "should depend on several clinical factors including rapid access to an endovascular center and the type of DOAC the patient is taking," the group said.

"In summary, the decision of how to treat a patient having an acute ischemic stroke while taking a DOAC is among the most complex and nuanced in acute stroke management. Uncertainty regarding time between the last DOAC dose and symptom onset and DOAC activity factor into risk of bleeding, risk of clotting, and chance of benefit from the use of a reversal agent prior to a thrombolytic agent," according to Czap and Grotta.

"A point-of-care test would go a long way to help clinicians with these areas of uncertainty, and development of such a test should be a priority. In the meantime, cases need to be carefully individualized and optimally managed by stroke specialists," the duo concluded.

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