March 2024: New In Coagulation

by Donna Castellone, MS, MT(ASCP)S • March 05, 2024

Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

Study Finds No Short-Term MACE, VTE Risk With JAK Inhibitors for Skin Diseases

Drugs that target the Janus kinase-signal transducer and activator of transcription (JAK-STAT) have been found that they do not increase the risk for cardiovascular or thrombotic complications in people undergoing treatment for a variety of dermatological conditions, at least in the short term.

Data from over 17,000 dermatological patients with different disorders from 45 placebo controlled randomized trials was analyzed. This meta-analysis included trials published up until June of 2023. Excluded were pooled analyses, long-term extension data, post hoc analyseis and pediatric trials. The studies had a minimum of 16 weeks follow up. Most (25) of the trials were phase 2b or phase 3 trials, 18 were phases 2-2b, and two were phase 1 trials. The studies included 12,996 participants, mostly with atopic dermatitis or psoriasis, who were treated with JAK-STAT inhibitors, which included baricitinib (2846 patients), tofacitinib (2470), upadacitinib (2218), abrocitinib (1904), and deucravacitinib (1492), among others. There were 4925 patients on placebo.

MACE occurred in 13 of the JAK-STAT inhibitor-treated patients and in four of those on placebo. VTE was reported in eight JAK-STAT inhibitor-treated patients and in one patient on placebo. The pooled incidence ratios for MACE and VTE were calculated as 0.20 per 100 person-exposure years (PEY) for JAK-STAT inhibitor treatment and 0.13 PEY for placebo. Results showed that there was no significant increase in major adverse cardiovascular events (MACE) in these patients. The results were also the same when the data was stratified according to dermatological condition being treated. These results are contrary to established sentiments. However, it is important to note that complications may be different in patients using for dermatological use versus rheumatologic use.

The ORAL Surveillance study showed all-cause mortality, cardiovascular events, VET and malignancy. This trial was conducted in patients with rheumatoid arthritis treat with tofacitinib or tumor necrosis factor inhibitor. Based on these results the FDA required information as a box warning stating the risks when using a JAK-STAT inhibitor in 2022. These patients are a different cohort than dermatological patients.

These results support the short term use of JAK-STAT inhibitors in patients with dermatological conditions with low cardiovascular risk profiles appear to be safe. Caution should be used with long term use as well as those from a high risk population.

Updates on Antithrombotics in Stroke, Migraine, and Long COVID

This is an overview of 6 studies that were published in December of 2023 on various topics:

A population based study that included 590,000 participants looked at the impact of the COVID-19 vaccination and if it prevents post or long-COVID syndrome. Half were vaccinated and had COVID-19, and the other were not vaccinated and also had COVID. Results showed that the incidence of post-COVID and long term COVID-19 in the vaccinated group was 0.4% versus 1.4% in the nonvaccinated group. These results strongly indicate the vaccination can prevent these syndromes.

Moat migraine sufferers (40%) have a prodromal phased with many different symptoms followed by a migraine attack. A crossover study of 518 people with migraines and prodromes were given an antagonist of the CGRP receptor, Ubrogepant, to determine if it could prevent the migraine when given during the prodromal phase. The primary endpoint was moderate or severe headache within 24 hours. Results showed 46% on ubrogepant vs 29% on placebo. This indicates that treatment during the prodromal phase can prevent headache following the prodromal phase.

Migraine (NEUROLOGY)
This study, also regarding migraines, looked at the efficacy of different migraine therapies for the treatment of acute migraine attacks. Data was analyzed from 270,000 migraine patients using a migraine app using ibuprofen as a reference. It showed that treatment was effective, with the most helpful being eletriptan helpful in 80% of patients followed by zolmitriptan and sumatriptan. Least effective were aspirin ibuprofen and paracetamol being helpful 38% of the time. Eletriptan is off patent and is cheap but is underutilized.

ESUS DOAC vs Aspirin
Two randomized trials NAVIGATE ESUS (embolic stroke of undetermined source) and RE-SPECT ESUS compared if rivaroxaban or dabigatran is superior to aspirin in the prevention of stroke in people with ESUS. ATTICUS study compared apixaban 5m daily with aspirin 100mg daily in high risk populations. The primary endpoint was apparent or silent strokes on MRI. After 12 months there was no difference in major bleeding or primary endpoint. A subgroup analysis demonstrated a trend in the efficacy in patients older than 75. A meta-analysis would provide more information.

People with a FXI deficiency have a decreased risk for stroke and MI and almost no increased risk for major bleeding. Milvexian is a small molecule drug that blocks coagulation factor XIia. This was investigated in a dose finding study compared with placebo. No difference was found between DAPT as monotherapy and combination of milvbxian on recurrent stroke, silent stokes as well as bleeding complications. Efficaacy of thie new drug needs to be shown in a larger phase 3 trial.

DAPT vs Aspirin in Stroke (NEJM)
DAPT of clopidogrel plus aspirin was compared with aspirin monotherapy in high risk TIA patients. Inclusion time was 72 hours and patients were treated for 90 days. There was a lower risk of ischemic events for the combination group with a benefit of 20%, but there was an increase in moderate or severe bleeding. Published studies have shown that combination therapy is superior to monotherapy only for the first 2 weeks because then the increased bleeding risk occurs. However this study looked at 90 days of combination therapy.

Q&A: Thromboembolism Management in Paroxysmal Nocturnal Hemoglobinuria

Thrombosis is a life threatening complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). This is a rare disorder caused by a PIGA mutation that is complement- driven hemolytic anemia resulting forrom the clonal expansion of these stem cells. Patients present with fatigue, dysphagia, abdominal pain and erectile dysfunction. Thrombosis can occur at any site, most common venous (80-85%) but in 15-20% of patients it can be arterial. The most common site is hepatic (40%) but cerebral thrombosis risk is also high. A pooled analysis of three trials show that the most common thrombosis is DVT (33%), followed by mesenteric (18%) and hepatic (16%). One thromboembolic event occurs in up to one-third of patients with PNH with thrombosis being the most common cause of death accounting for up to 50% of mortality in untreated patients.

Patients may be treated with vitamin K inhibitors, or DOACs, and if life threatening thrombolytic therapy. In those with severe thrombocytopenia, platelets may need to be transfused.

The pathophysiologic mechanism includes platelet activation, complement mediated hemolysis, impaired nitric oxide bioavailability, impairment of the fibrinolytic system and inflammatory mediators. Treatment with complement inhibitors eculizumab and ravulizumab are the treatment of choice. These drugs have reduced long term complication; however the risk of thrombosis remains high in particular during times of breakthrough hemolysis. When thrombosis occurs, anticoagulation should be given simultaneously. A new drug, a pegylated peptide, pegcetacoplan has been approved. It inhibits both intravascular and extravascular hemolysis in adults. Iptacopan, and oral factor B inhibitor has also received FDA approval.

In patients with well controlled PNH without any other thrombosis-predisposing factors anticoagulation is usually given for 3- 6 months which reduces the risk of bleeding and thrombocytopenia. In patients who do have a thrombotic event while on therapy anticoagulation is indefinite. If patients have not had a thrombotic complication, nor placed in a situation that exacerbates a thrombotic event, prophylactic anticoagulation lacks high quality evidence.

Anticoagulant Falls Short for Secondary Stroke Prevention in Atrial Cardiopathy

The ARCADIA was a multicenter phase III trial conducted at 185 sites. A total of 1015 participants with an average age of 68, which 54.3% were female. Of these 30% had diabetes, 3/4 had hypertension and 10% had known ischemic heart disease. Time from stroke onset to randomization was average of 50 days with a follow up of 1.8 years. Patients were randomized to apixaban 5 mg twice/day versus aspirin 81 mg daily.

The ARCADIA trial determined that OAC was not found to perform better than low dose aspirin for secondary stroke prevention in patients with left atrial cardiopathy with absent AF. Recurrent rate of stroke was 4.4% despite being randomized to apixaban or aspirin. The trial had been stopped since they couldn't reach their target of 1100 participants. There was no indication of safety concerns and there were low rates of symptomatic ICH and other hemorrhage at 2 years of follow up. These results seemed to contradict prior observational studies that linked markers of atrial cardiopathy with the risk of ischemic stroke.

Late Tenecteplase Not Beneficial for Stroke Patients With LVOs

The TIMELESS trial was a multicenter (112 sites in US and Canada) that enrolled patients with ischemic stroke. Enrollment criteria included evidence of an occlusion inm the middle cerebral artery or internal carotid artery with salvageable tissue on CT perfusion imagining or MRI. There were 458 participants who received Tenecteplase or placebo given 4.5 to 24 hours after patient was last known to be well. Median age was 72 with 53.5% being women.

Results of the study showed that stroke patient did not benefit clinically from having the window of Tenecteplase extended beyond the first few hours of stroke onset. Functional outcomes at 90 days were the same whether patients were randomized to tenecteplase or placebo. Also similar were the 90 day rate of mortality (19.7% vs 18.2%) and ICH (3.2% vs 2.3%).

Subgroup analysis showed an appearance that people with occlusions in the M1 segment had good outcomes and may be beneficial in these patients when administered in the 4.5-24 hour window, but was unlikely to help patients with large vessel occlusions who do not undergo thrombectomy. Up to 77.3% of patients underwent thrombectomy. The trial was underpowered to make conclusions in people who did not receive endovascular therapy. Patients with LVOs were excluded from the trial.

Tirofiban a Better Option for Ischemic Stroke When Lytics and Thrombectomy Aren't?

The TREND trial demonstrated that in acute ischemic stroke patients without thrombolytic or thrombectomy, tirofiban started within 24 hours of symptoms was better than just aspirin. The trial enrolled 426 patients in China who were age 18-80 with presumed non-cardioembolic ischemic stroke. Subjects were randomly assigned IV tirofiban or aspirin 150-300 mg/day for 72 hours followed by aspirin alone or with clopidogrel. This therapy also reduced the incidence of neurological deterioration to 4.2% vs 13.2% in patients on aspirin. Functional outcomes at 90 days were similar. Many patients have contraindications to IV thrombolytics. There were no casesd of symptomatic ICH or severe bleeding and mortality was similar between groups. A trial should be conducted that compares clopidogrel and aspirin against tirofiban with aspirin.

The RESCUE BT2 trial also showed that tirofiban was superior to aspirin in heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium sized cerebral vessels. The benefit and safety of more aggressive antiplatelet therapy with moderate to severe stroke has not yet been established. This study should help to confirm those findings.

Limitations included studies being conducted on only Chinese populations and should be conducted on a broader population.

Adjunctive Thrombolysis Doesn't Boost tPA Benefits

The MOST trial showed that thrombolysis with either argatroban or eptifibatide for acute ischemic stroke did not boost efficacy and contributed to risk. The placebo yielded the best 90 day utility weighted modified Rankin Scale (cRS) scores with a mean offo 6.8 as compared to argatroban at 5.2 and eptifibatide at 6.3. Results were disappointing.

There were 514 patients randomized with a pre-thrombolysis score of 6 or greater, of those 421 completed the trial. Within 3 hours of stroke onset, patients received recombinant tPA - alteplase at 0.9 mg/kg or tenecteplase at 0.25 mg/kg. They were randomized within 60 minutes and no later than 75 minutes post thrombolytic bolus. The argatroban group (n=59) received a 100-µg/kg bolus and a 12-hour infusion at 3 µg/kg/min. The 227 patients in the eptifibatide group got a 135-µg/kg bolus and a 2-hour infusion at 0.75 µg/kg/min followed by a 10-hour saline infusion. The 228 placebo-group patients got saline as a bolus and 12-hour infusion.

All cause mortality with argatroban was significantly more common than placebo (24.1 vs 78%) while the rate was also found to be high with eptifibatide at 11.8%. No deaths were reported to be caused by the study drug, ICH rates were high.

Limitations included a small number of argatroban patients, a single blind design and the unknown impact or adjunctive intra-arterial antithrombotic medications in endovascular thrombectomy patients.

After Cervical Artery Dissection, Early Anticoagulant Might Be Better

An observational study revealed that anticoagulation performed at least as well as antiplatelet medication for stroke prevention post cervical artery dissection. At 30 days and up to 180 days, subsequent ischemic stroke was numerically but not significantly less common with anticoagulation than with antiplatelets.

In patients with occlusive dissection, anticoagulation had a significant advantage. It did not present with a risk at 30 days, however at 180 days the risk was substantial. Switching to antiplatelets before 180 days may lower the risk of bleeding.

Only 2% of ischemic strokes are caused by cervical artery dissection, however up to 25% of them occur in young adults 50 years and younger. Up to 3% have subsequent strokes, therefore guidelines recommend antithrombotic therapy for 3-6 months, but does not specify anticoagulation or antiplatelet.

Prior trials (CADISS and TREAT-CAD) compared vitamin K antagonists with antiplatelet therapy after cervical artery dissection. However the studies fell short., Oone suggested anticoagulation was superior but it was underpowered and the other failed to show non-inferiority of aspirin.

STOP-CAD looked at 4023 patients from 63 sites in 16 countries. There were 3636 patients who received only therapeutic anticoagulation, with 2453 patients getting antiplatelets either single or DAPT. Results were similar between the DOACs and vitamin K antagonists. A retrospective study can result in a potential for bias and while not giving definitive answers, it does point in the direction of an answer. Prospective studies are needed.

Hot Flashes, Migraine Tied to Higher Risk of Stroke, Heart Disease

An analysis of the CARDIA study showed that a history of migraine combined with persistent hot flashesd was associated with a higher risk for cardiovascular disease and stroke by almost two fold when compared to women without migraines and minimal hot flashes. However, when adjusting for risk factors of blood pressure and cholesterol the risks were attenuated for both cardiovascular disease risk (HR 1.51) and stroke risk (HR 1.70). If only one condition was present there was no increased risk, however as women enter middle age, the combination may represent abnormal risk factors. It is important to be able to predict which women will experience adverse outcomes.

The analysis included 1954 women who were followed for 15 years with a mean age of 40.5 years. In this cohort 835 had minimal vasomotor symptoms, 521 had increasing vasomotor symptoms and 598 had persistent symptoms. There were a total of 42 strokes and 81 incidents of cardiovascular disease. Migraines were higher in women with persistent vasomotor symptoms (23 vs 14%). Those who reported persistent vasomotor symptoms were more likely black, smokers, have less than a high school education, and less likely to use oral contraceptives, but more likely to use exogenous hormone therapies as well as have histories of hysterectomy or oophorectomy.


Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial

Manel Mendoza, PhD; Erika Bonacina, MD; Pablo Garcia-Manau, MD; et alMonica López, MD; Sara Caamiña, MD; Àngels Vives, PhD; Eva Lopez-Quesada, PhD; Marta Ricart, MD; Anna Maroto, PhD; Laura de Mingo, MD; Elena Pintado, MD; Roser Ferrer-Costa, PhD; Lourdes Martin, MD; Alicia Rodríguez-Zurita, MD; Esperanza Garcia, MD; Mar Pallarols, MD; Laia Vidal-Sagnier, MD; Mireia Teixidor, MD; Carmen Orizales-Lago, MD; Adela Pérez-Gomez, MD; Vanesa Ocaña, MD; Linda Puerto, MD; Pilar Millán, MD; Mercè Alsius, MD; Sonia Diaz, MD; Nerea Maiz, PhD; Elena Carreras, PhD; Anna Suy, PhD

JAMA. 2023;329(7):542-550. doi:10.1001/jama.2023.0691


Importance Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy.

Objective To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase–1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia.

Design, Setting, and Participants Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n=968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n=473; control: n=463). Follow-up was until delivery for all participants.

Interventions Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group).

Main Outcomes and Measures Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%.

Results Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, −0.25% [95% CI, −1.86% to 1.36%]), indicating noninferiority.

Conclusions and Relevance Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation

Jeff S Healey, Renato D Lopes, Christopher B Granger, Marco Alings, Lena Rivard, William F McIntyre, Dan Atar, David H Birnie, Giuseppe Boriani, A John Camm, David Conen, Julia W Erath, Michael R Gold, Stefan H Hohnloser, John Ip, Josef Kautzner, Valentina Kutyifa, Cecilia Linde, Philippe Mabo, Georges Mairesse, Juan Benezet Mazuecos, Jens Cosedis Nielsen, Francois Philippon, Marco Proietti, Christian Sticherling, Jorge A Wong, David J Wright, Ignatius G Zarraga, Shelagh B Coutts, Andrew Kaplan, Marta Pombo, Felix Ayala-Paredes, Lizhen Xu, Kim Simek, Sandra Nevills, Rajibul Mian, Stuart J Connolly; ARTESIA Investigators

N Engl J Med 2024 Jan 11;390(2):107-117.
doi: 10.1056/NEJMoa2310234. Epub 2023 Nov 12.


Background: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.

Methods: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason).

Results: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.

Conclusions: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

Long-term Clopidogrel Has Advantages After Coronary Stenting

Hirotoshi Watanabe, MD, January 2, 2023, Journal of the American College of Cardiology

At 5 years, clopidogrel was noninferior to aspirin for net adverse clinical events in patients who have undergone percutaneous coronary intervention (PCI) using drug-eluting stents but was superior to aspirin in reducing secondary endpoints of myocardial infarction (MI) and ischemic stroke, a new analysis showed.

One-year results from the randomized, multicenter Short and Optimal Duration of Dual Antiplatelet Therapy 2 (STOPDAPT-2) trial showed clopidogrel monotherapy after a month of dual antiplatelet therapy (DAPT) substantially reduced major bleeding compared with continued DAPT using clopidogrel and aspirin, without an increase in cardiovascular events, among Japanese patients undergoing PCI.

According to the trial protocol, clopidogrel monotherapy was continued in the 1-month DAPT group (clopidogrel group), while the 12-month DAPT group was shifted to aspirin monotherapy (aspirin group). The authors reported 5-year results in 3005 patients — mean age 68.6 years, 22.3% women, and 38.3% with acute coronary syndrome at baseline.

The primary endpoint was net adverse clinical events, defined as a composite of cardiovascular outcomes (death from cardiovascular causes, MI, stent thrombosis, stroke) and major or minor bleeding. Secondary outcomes included the separate cardiovascular and bleeding components of the primary endpoint and newly diagnosed cancer because there's some suggestion aspirin might protect against colorectal cancer.


  • The clopidogrel group was noninferior, but not superior, to the aspirin group for the primary endpoint (11.75% vs 13.57%; hazard ratio [HR], 0.85; 95% CI, 0.70-1.05; P for noninferiority < .001; P for superiority = .13).
  • The clopidogrel group was superior to the aspirin group for the major secondary cardiovascular endpoint (8.61% vs 11.05%; HR, 0.77; 95% CI, 0.61-0.97; P for noninferiority < .001; P for superiority = .03), mainly driven by reduction in MI and ischemic stroke.
  • The cumulative 5-year incidence of major secondary bleeding was not lower in the clopidogrel group (4.44% vs 4.92%; HR, 0.89; 95% CI, 0.64-1.25; P = .51), possibly due to the high prevalence of proton pump inhibitor use (79%), said the authors, nor was the incidence of newly diagnosed cancer.


"Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI," the authors wrote.

"This important study confirms that ischemic protection post-PCI is better ensured by clopidogrel than aspirin from 1 month to 5 years," wrote Anne Bellemain-Appaix, MD, Cardiology Department, Antibes Hospital, Antibes, and Sorbonne University, Paris, France, and a colleague in an accompanying editorial, adding that beyond 1 month, DAPT de-escalation to a P2Y12 inhibitor alone "may become the new standard of care among select, if not most, patients."

LIMITATIONS: Although overall adherence to antiplatelet therapy was more than 80% during follow-up, participants with clinical events such as revascularization often changed antiplatelet therapy, so they may not have been treated as allocated. The study enrolled only Japanese patients, and there might be risk differences in cardiovascular and bleeding events across ethnicities. Researchers didn't have data on the status of medications other than antithrombotic therapy. The study didn't include a formal cost-effectiveness analysis, which would be crucial for adopting a lifelong treatment (aspirin is relatively inexpensive).

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial

Hooman Kamel, MD; W. T. Longstreth Jr, MD; David L. Tirschwell, MD; et alRichard A. Kronmal, PhD; Randolph S. Marshall, MD; Joseph P. Broderick, MD; Rebeca Aragón García, BS; Pamela Plummer, MSN; Noor Sabagha, RPH; Qi Pauls, MS; Christy Cassarly, PhD; Catherine R. Dillon, MS; Marco R. Di Tullio, MD; Eldad A. Hod, MD; Elsayed Z. Soliman, MD; David J. Gladstone, MD; Jeff S. Healey, MD; Mukul Sharma, MD; Seemant Chaturvedi, MD; L. Scott Janis, PhD; Balaji Krishnaiah, MD; Fadi Nahab, MD; Scott E. Kasner, MD; Robert J. Stanton, MD; Dawn O. Kleindorfer, MD; Matthew Starr, MD; Toni R. Winder, MD; Wayne M. Clark, MD; Benjamin R. Miller, MD; Mitchell S. V. Elkind, MD; for the ARCADIA Investigators

JAMA. Published online February 7, 2024. doi:10.1001/jama.2023.27188


Importance Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation.

Objective To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy.

Design, Setting, and Participants Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 μV x ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium.

Interventions Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508).

Main Outcomes and Measures The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage.

Results With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]).

Conclusions and Relevance In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin.

Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis

Johannes Kaesmacher, MD, PhD; Fabiano Cavalcante, MD; Manon Kappelhof, MD, PhD; et alKilian M. Treurniet, MD, PhD; Leon Rinkel, MD; Jianmin Liu, MD; Bernard Yan, DMedSci; Wenjie Zi, MD; Kazumi Kimura, MD, PhD; Omer F. Eker, MD, PhD; Yongwei Zhang, MD; Eike I. Piechowiak, MD; Wim van Zwam, MD, PhD; Sheng Liu, MD; Daniel Strbian, MD, MSc, PhD; Maarten Uyttenboogaart, MD, PhD; Tomas Dobrocky, MD; Zhongrong Miao, MD; Kentaro Suzuki, MD, PhD; Lei Zhang, MD; Robert van Oostenbrugge, MD, PhD; Thomas R. Meinel, MD, PhD; Changwei Guo, MD; David Seiffge, MD; Congguo Yin, MD; Lukas Bütikofer, PhD; Hester Lingsma, PhD; Daan Nieboer, PhD; Pengfei Yang, MD; Peter Mitchell, MMed; Charles Majoie, MD, PhD; Urs Fischer, MD, MSc; Yvo Roos, MD, PhD; Jan Gralla, MD, MSc; for the IRIS Collaborators

JAMA. Published online February 7, 2024. doi:10.1001/jama.2024.0589


Importance The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy.

Objective To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset.

Design, Setting, and Participants Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313).

Exposure Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone.

Main Outcomes and Measures The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT.

Results In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, −3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes.

Conclusions and Relevance In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

Dual Antiplatelet Therapy De-Escalation in Stabilized Myocardial Infarction With High Ischemic Risk: Post Hoc Analysis of the TALOS-AMI Randomized Clinical Trial

Myunhee Lee, MD; Sungwook Byun, MD, PhD; Sungmin Lim, MD, PhD; et alEun Ho Choo, MD, PhD; Kwan Yong Lee, MD, PhD; Donggyu Moon, MD; Ik Jun Choi, MD, PhD; Byung-Hee Hwang, MD, PhD; Chan Joon Kim, MD, PhD; Mahn-Won Park, MD, PhD; Yun Seok Choi, MD, PhD; Hee-Yeol Kim, MD, PhD; Ki-Dong Yoo, MD, PhD; Doo-Soo Jeon, MD, PhD; Hyeon Woo Yim, MD, PhD; Kiyuk Chang, MD, PhD; for the TALOS-AMI Investigators


Importance In patients with acute myocardial infarction (AMI) who have high ischemic risk, data on the efficacy and safety of the de-escalation strategy of switching from ticagrelor to clopidogrel are lacking.

Objective To evaluate the outcomes of the de-escalation strategy compared with dual antiplatelet therapy (DAPT) with ticagrelor in stabilized patients with AMI and high ischemic risk following percutaneous coronary intervention (PCI).

Design, Setting, and Participants This was a post hoc analysis of the Ticagrelor vs Clopidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) trial, an open-label, assessor-blinded, multicenter, randomized clinical trial. Patients with AMI who had no event during 1 month of ticagrelor-based DAPT after PCI were included. High ischemic risk was defined as having a history of diabetes or chronic kidney disease, multivessel PCI, at least 3 lesions treated, total stent length greater than 60 mm, at least 3 stents implanted, left main PCI, or bifurcation PCI with at least 2 stents. Data were collected from February 14, 2014, to January 21, 2021, and analyzed from December 1, 2021, to June 30, 2022.

Intervention Patients were randomly assigned to either de-escalation from ticagrelor to clopidogrel or ticagrelor-based DAPT.

Main Outcomes and Measures Ischemic outcomes (composite of cardiovascular death, myocardial infarction, ischemic stroke, ischemia-driven revascularization, or stent thrombosis) and bleeding outcomes (Bleeding Academic Research Consortium type 2, 3, or 5 bleeding) were evaluated.

Results Of 2697 patients with AMI (mean [SD] age, 60.0 [11.4] years; 454 [16.8%] female), 1371 (50.8%; 684 assigned to de-escalation and 687 assigned to ticagrelor-based DAPT) had high ischemic risk features and a significantly higher risk of ischemic outcomes than those without high ischemic risk (1326 patients [49.2%], including 665 assigned to de-escalation and 661 assigned to ticagrelor-based DAPT) (hazard ratio [HR], 1.74; 95% CI, 1.15-2.63; P = .01). De-escalation to clopidogrel, compared with ticagrelor-based DAPT, showed no significant difference in ischemic risk across the high ischemic risk group (HR, 0.88; 95% CI, 0.54-1.45; P = .62) and the non–high ischemic risk group (HR, 0.65; 95% CI, 0.33-1.28; P = .21), without heterogeneity (P for interaction = .47). The bleeding risk of the de-escalation group was consistent in both the high ischemic risk group (HR, 0.64; 95% CI, 0.37-1.11; P = .11) and the non–high ischemic risk group (HR, 0.42; 95% CI, 0.24-0.75; P = .003), without heterogeneity (P for interaction = .32).

Conclusions and Relevance In stabilized patients with AMI, the ischemic and bleeding outcomes of an unguided de-escalation strategy with clopidogrel compared with a ticagrelor-based DAPT strategy were consistent without significant interaction, regardless of the presence of high ischemic risk.