NIH halts arm of clinical trial evaluating a potential stroke treatment

 You're now more up-to-date than your stroke medical 'professionals'

NIH halts arm of clinical trial evaluating a potential stroke treatment

Study found low-dose rivaroxaban to be unsafe and ineffective compared to standard of care.The National Institutes of Health (NIH) has stopped an investigational treatment arm of the Comparison of Anti-coagulation and Anti-platelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) study following a regular review by the Data Safety and Monitoring Board (DSMB). The DSMB is an independent group of experts that regularly check if the study is safe. NIH’s National Institute of Neurological Disorders and Stroke, the trial’s funder, accepted the DSMB recommendation that CAPTIVA discontinue the low-dose rivaroxaban arm of the trial due to an increase in safety events and evidence of futility, a pre-specified stopping point to enable the study to end if early results showed the treatment is unlikely to help people. Rivaroxaban is a U.S. Food and Drug Administration-approved anticoagulant medication used to treat or prevent blood clots. All study sites that have active participants randomized to the discontinued arm have received instructions for drug discontinuation. Study participants who have completed their evaluation of the discontinued arm will be contacted by the site where they received treatment. Participant safety remains NIH’s top priority.The CAPTIVA study is a large, two-stage, double-blind randomized trial in participants age 30 and older with a stroke attributed to 70-99% narrowing, or stenosis, of a major intracranial artery. The study is testing whether either of two new treatments works better than the current treatment to prevent another stroke. The study, part of NIH’s StrokeNet is in the midst of enrolling and evaluating up to 1,683 volunteers at over 100 study sites over a four-year period. Participants were randomized 1:1:1 to one year of treatment with:

1. Ticagrelor (180 mg loading dose, then 90 mg twice daily) plus aspirin (81 mg daily)
2. Low-dose rivaroxaban (2.5 mg twice daily) plus aspirin (81 mg daily)
3. Clopidogrel (600 mg loading dose, then 75 mg daily) plus aspirin (81 mg daily)

In addition, participants will receive intensive risk factor management and lifestyle coaching. They will be evaluated at one month, four months, eight months, and one year after randomization into one of the study arms. At these intervals, participants will have their blood pressure checked, risk factors optimized and will be assessed for study outcomes.

CAPTIVA will not determine which new treatment is best. It will only show if either new treatment is better than what doctors currently use. Comparing the two new treatments directly would require many more patients. Nevertheless, CAPTIVA will provide important safety and efficacy data on both novel therapies.

The CAPTIVA Study and NIH’s StrokeNet are funded by NIH’s NINDS.

About the National Institute of Neurological Disorders and Stroke (NINDS): NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. https://www.ninds.nih.gov

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.

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis

Who the fuck are the blithering idiots that are worried about standard of 'care'? Survivors want to know about standard of RESULTS  you fucking idiots! 

When you realize the absolute idiocy in stroke you legitimately get mad. Tell me exactly why I shouldn't be mad!

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis

Thalia S. Field,

Vanessa Dizonno,

Mohammed A. Almekhlafi,

Fouzi Bala,

Ibrahim Alhabli,

Hubert Wong,

Monica Norena,

Maria Karina Villaluna,

Princess King-Azote,

Namali Ratnaweera,

… See all authors

and on behalf of the SECRET Investigators

Originally published7 Sep 2023https://doi.org/10.1161/STROKEAHA.123.044113Stroke. 2023;0

Abstract

Background:

Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes.

Methods:

This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0–3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365.

Results:

Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5–73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180.

Conclusions:

Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03178864.

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Anticoagulation Again Flops for Outpatient COVID-19

Which is interesting since anti-coagulation with heparin was considered state of the art earlier.  But then this is outpatient not hospitalized patients. So DEMAND YOUR DOCTOR KNOW EXACTLY WHAT TO DO FOR YOUR COVID-19.

Heparin:

Why I'm getting heparin.  Heparin binds to cells at a site adjacent to ACE2, the portal for SARS-CoV-2 infection, and "potently" blocks the virus, which could open up therapy options.

Anticoagulation Again Shown to Improve Survival in COVID-19 Patients;-Mortality risk about 50% lower

The latest here:

Anticoagulation Again Flops for Outpatient COVID-19

Largest-yet RCT shows no benefit for non-hospitalized symptomatic patients despite elevated risk

by Crystal Phend, Contributing Editor, MedPage Today November 8, 2022

CHICAGO -- For outpatient COVID-19, prophylactic anticoagulation with rivaroxaban (Xarelto) did not improve outcomes in elevated thrombotic risk patients, the PREVENT trial showed.

Compared with placebo, giving the direct-acting oral anticoagulant (DOAC) for 35 days in non-hospitalized patients with symptomatic COVID-19 who had at least one risk factor for thrombosis didn't reduce thromboembolic events or all-cause hospitalization or death in the primary intent-to-treat analysis.

The rate was 3.4% with rivaroxaban versus 3.0% with placebo, based on 22 and 19 events, respectively, among the more than 1,200 trial participants (HR 1.16, 95% CI 0.63-2.15), Gregory Piazza, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, reported at the American Heart Association meeting in Chicago.

"With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in non-hospitalized patients with symptomatic COVID-19," he told attendees, noting that the trial was stopped early at about one-third of planned enrollment due to waning pandemic numbers and severity.

That's a message that squares with other anticoagulant trials in outpatient care for COVID-19, noted Renato Lopes MD, PhD, of Duke Clinical Research Institute in Durham, North Carolina, who served as study discussant at the late-breaking clinical trial session.

Meta-analysis with the almost universally negative trials that have emerged thus far suggested no benefit (OR 0.93, 95% CI 0.70-1.23) for the primary endpoint, albeit diverse across trials, or for mortality (OR 0.64, 95% CI 0.25-1.61).

"The results of this trial, in the light of the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19," Lopes said.

PREVENT randomized 1,284 symptomatic patients with a positive laboratory antigen or PCR test for SARS-CoV-2 recruited through integrated health networks in the U.S. to once daily rivaroxaban (10 mg) or placebo, stratified by number of days from positive test to randomization. Participants were followed for outcomes without any lab or office visits, utilizing electronic case report forms and electronic medical records collected only through telehealth or home visits.

Patients were not enrolled if the initial care plan included hospitalization. Enrollment criteria also selected for a higher thrombotic risk group by requiring at least one of the following risk factors:

• Age ≥ 60 years
• Prior history of venous thromboembolism (VTE), thrombophilia, coronary or peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes requiring medication, or heart failure
• BMI ≥35 kg/m²
• Elevated D-dimer

The most common risk factors were older age, obesity, and diabetes. About a quarter of participants had at least two risk factors. Mean age was 56 years; nearly 30% of participants were non-white and about 60% were female.

The primary efficacy endpoint was first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

For that endpoint, the modified intended-to-treat analysis yielded a shift in directionality compared with the intent-to-treat analysis, albeit not statistically significant, with a rate of 2.0% with rivaroxaban versus 2.7% with placebo (HR 0.75, 95% CI 0.35-1.58). Piazza chalked that up to more hospitalizations before receiving study drug in the rivaroxaban group, while Lopes suggested the difference deserves further investigation.

The first major secondary outcome of the composite of symptomatic VTE, arterial thrombotic events, and all-cause mortality likewise showed no significant difference. A post hoc exploratory analysis suggested fewer combined symptomatic VTE and arterial thrombotic events, particularly ischemic stroke, but Lopes urged caution with such non-prespecified analyses.

In terms of safety, there were no fatal or critical site bleeds in the trial and a "significant but modest" increase in nonmajor clinically relevant bleeds with rivaroxaban versus placebo.

"We've seen explosion of observational data in the beginning of pandemic suggesting that patients with COVID-19 might benefit from a more intense form of anticoagulation; however, we also learned to be cautious about observational data when discussing treatment effects," Lopes noted.

That the findings were the opposite of what might have been guessed initially in the pandemic, he said, was "illustrating one more time why we need randomized trials, since they are the only reliable way to guide medical decisions in clinical practice."

• 

  Crystal Phend is a contributing editor at MedPage Today. Follow

Disclosures

The trial was sponsored by Janssen.

Piazza disclosed research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen and Boston Scientific as well as consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

Lopes disclosed relationships with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis, Bayer, Novo Nordisk, and Boehringer Ingelheim.

Primary Source

American Heart Association

Source Reference: Piazza G "Rivaroxaban to reduce the risk of major venous and arterial thrombotic events, hospitalization and death in medically ill outpatients with COVID-19: Primary results of the PREVENT-HD randomized clinical trial" AHA 2022.

Apixaban Associated With Lower Risk of Stroke Than Rivaroxaban in Patients With AF, Valvular Heart Disease

For discussion with your doctor.

Apixaban Associated With Lower Risk of Stroke Than Rivaroxaban in Patients With AF, Valvular Heart Disease

Among patients with atrial fibrillation (AF) and valvular heart disease (VHD), patients receiving apixaban had a lower risk for ischaemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban, according to a study published in Annals of Internal Medicine.

“The lack of clinical trial evidence and wide use of both drugs in patients with AF and VHD calls for real-world evidence that can guide treatment selection in clinical practice,” said Ghadeer Dawwas, PhD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

For the real-world study, the researchers analysed data from a commercial health insurance database (January 2013-December 2020) and identified 9,947 patients who had recently started taking apixaban and compared them with another 9,947 patients newly taking rivaroxaban. All patients were matched for age and other characteristics that could affect outcomes.

When compared with rivaroxaban, apixaban was associated with a lower rate of ischeamic stroke or systemic embolism (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.40-0.80) and bleeding (HR = 0.51; 95% CI, 0.41-0.62).

The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation

The researchers calculated that the rate of stroke or systemic embolism per patient per year of follow-up was 0.91% for rivaroxaban users compared with 0.52% for apixaban users.

“Until evidence from randomized controlled trials becomes available, we believe clinicians should consider our findings when selecting anticoagulants in patients with AF and VHD,” said senior author Sean Hennessy, PhD, University of Pennsylvania.

Reference: https://www.acpjournals.org/doi/10.7326/M22-0318

SOURCE: University of Pennsylvania School of Medicine

Apixaban Associated With Lower Risk of Stroke Than Rivaroxaban in Patients With AF, Valvular Heart Disease

 For discussion with your doctor.

Apixaban Associated With Lower Risk of Stroke Than Rivaroxaban in Patients With AF, Valvular Heart Disease

Among patients with atrial fibrillation (AF) and valvular heart disease (VHD), patients receiving apixaban had a lower risk for ischaemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban, according to a study published in Annals of Internal Medicine.

“The lack of clinical trial evidence and wide use of both drugs in patients with AF and VHD calls for real-world evidence that can guide treatment selection in clinical practice,” said Ghadeer Dawwas, PhD, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

For the real-world study, the researchers analysed data from a commercial health insurance database (January 2013-December 2020) and identified 9,947 patients who had recently started taking apixaban and compared them with another 9,947 patients newly taking rivaroxaban. All patients were matched for age and other characteristics that could affect outcomes.

When compared with rivaroxaban, apixaban was associated with a lower rate of ischeamic stroke or systemic embolism (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.40-0.80) and bleeding (HR = 0.51; 95% CI, 0.41-0.62).

The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation

The researchers calculated that the rate of stroke or systemic embolism per patient per year of follow-up was 0.91% for rivaroxaban users compared with 0.52% for apixaban users.

“Until evidence from randomized controlled trials becomes available, we believe clinicians should consider our findings when selecting anticoagulants in patients with AF and VHD,” said senior author Sean Hennessy, PhD, University of Pennsylvania.

Reference: https://www.acpjournals.org/doi/10.7326/M22-0318

SOURCE: University of Pennsylvania School of Medicine

Rivaroxaban versus aspirin on functional and cognitive outcomes after embolic stroke of undetermined source: NAVIGATE ESUS trial

 I understood nothing in here that helps survivors recover.

Rivaroxaban versus aspirin on functional and cognitive outcomes after embolic stroke of undetermined source: NAVIGATE ESUS trial

Author links open overlay panelJackieBosch^a

Lesly A.Pearce^bMukulSharma^cMichelleCanavan^dWilliam N.Whiteley^eRobertMikulík^fHardiMundl^gSalimYusuf^hRobert G.Hart^hMartin J.O'Donnellⁱ

https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106404Get rights and content

Abstract

Background

The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke.

Aims

To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes.

Methods

Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke.

Results

Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition.

Conclusions

Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.

 

Real-World Rivaroxaban Data Show Stroke, Bleeding Risk Low

At first I wouldn't have gone on this because of a lack of a reversal agent but since Dec. 2015 Praxbind (idrucizumab) is approved.
https://www.medpagetoday.com/cardiology/arrhythmias/73816?

Global analysis also showed low treatment discontinuation

• by Salynn Boyles, Contributing Writer July 02, 2018
• This article is a collaboration between MedPage Today® and:
  

In a real-world analysis involving more than 11,000 patients with atrial fibrillation from 47 countries, the risk for stroke and major bleeding in users of the direct oral anticoagulant rivaroxaban (Xarelto) was similar to or lower than that seen in the pivotal clinical trials, researchers report.
The one-year rate of stroke or systemic embolism was only 1.0% and the rate of major bleeding was 1.7% in the large, pre-planned pooled analysis of three previously described prospective, observational, international, non-interventional studies that comprised the XANTUS program.
"Overall, rivaroxaban showed a favorable safety profile, with greater than 96% of the pooled rivaroxaban population not experiencing any of the events of treatment-emergent major bleeding, stroke/non-CNS systemic embolism (SE) or all-cause death over a follow-up period of approximately one year," wrote Paulus Kirchhof, MD, of the University of Birmingham in England, and colleagues in the Journal of the American College of Cardiology, published online July 2.
The researchers noted that the XANTUS program offers a unique source of real-world data on the use of rivaroxaban for stroke prevention in Afib patients. The three prospective studies included patients from Western and Eastern Europe, Canada and Israel (XANTUS trial), the Asia-Pacific region (XANAP trial), and Eastern Europe the Middle East, Africa and Latin America (XANTUS-EL).
Patients were prescribed the direct oral anticoagulant (DOAC) rivaroxaban in accordance with country-specific drug approvals.
Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and non-major bleeding.
Overall, 11,121 patients were included in the analysis (mean age 70.5±10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%).
Event rates, calculated as one event per 100 patient-years, were:

• Major bleeding: 1.7/100 patient-years; 95% CI 1.5-2.0)
• All-cause death: 1.9/100 patient-years (95% CI 1.6-2.2)
• Stroke or systemic embolism: 1.0/100 patient-years (95% CI 0.8 to 1.2)

Regional differences were considerable. For instance, major bleeding rates varied from 0.7 per 100 patient-years in Latin America verses 2.3 per 100 patient-years in a group including Western Europe, Canada, and Israel.
One-year treatment persistence was 77.4%, with East Asia showing the lowest rate (66.4%) and Eastern Europe the highest (84.4%).
The researchers concluded that the real-world treatment analysis showed low bleeding and stroke rates in rivaroxaban-treated patients with Afib. Low rates of treatment discontinuation were seen throughout the world and results were broadly consistent across regions.
Study limitations cited by the researchers included the exclusion of patients from the United States and China (with the exception of Hong Kong) from the analysis and possible selection bias, given that patients had to agree to participate in the study.
In an accompanying editorial, cardiologist Jeff Healey, MD, of McMaster University in Hamilton, Ontario, noted that the study population was very representative of the practices they came from.
"The age and the proportion of patients with hypertension, diabetes and prior stroke in this cohort are quite similar to another multinational registry enrolling patients from the emergency department, suggesting that these patients are reasonably representative of the larger population of individuals with AF," he wrote. "Thus, like may observational studies, the current study population is a reasonable balance of what is practical and what is ideal."
Kirchhof and colleagues noted that the patients included in the observational studies had similar characteristics to those included in the clinical trials.
Healey wrote that the analysis confirms that "the use of rivaroxaban is largely in accordance with published guidelines, and persistence with therapy at one year was high, at least in the practices of participating physicians."
"Although these data are not population-based, they represent what a typical clinician might expect if they utilize a DOAC medication in accordance with local product labeling and practice guidelines, and are a testament to the successful introduction of DOACs into the clinical practice," Healey wrote.
"Although the current work does not help us to understand why the translation into clinical practice was so successful, easy-to-use medications, clear high-quality randomized trials, thoughtful practice guidelines, and coordinated physician education all likely played a role."

The XANTUS resarch program was funded by Bayer.
Paulus Kirchhof has received research support from Bayer HealthCare, AstraZeneca, Bioscnece Webster, Boehringer Ingelheim and other pharmaceutical companies.

last updated 07.03.2018

• Primary Source

  Journal of the American College of Cardiology

  Source Reference: Kirchhof P, et al "Global prospective safety analysis of rivaroxaban" JACC 2018; DOI: j.jacc.2018.04.058.

• Secondary Source

  Journal of the American College of Cardiology

  Source Reference: Healey JS "Stroke prevention in atrial fibrillation: what real world and what do real-world data reveal?" JACC 2018; DOI: 10.1016/j.jacc.2018.04.057.

NOAC Not Better Against Cryptogenic Stroke Recurrence

What is your doctor keeping you on after your stroke to prevent the next one?
https://www.medpagetoday.com/cardiology/strokes/72909?

Rivaroxaban had no advantage over aspirin, and increased bleeding risk in trial

• by Crystal Phend, Senior Associate Editor, MedPage Today May 16, 2018
• This article is a collaboration between MedPage Today® and:
  

Rivaroxaban (Xarelto) was not better than aspirin for preventing recurrence of ischemic strokes without a known source of the emboli, but it did increase bleeding risk, the NAVIGATE ESUS trial found.
For the primary endpoint, the non-vitamin K antagonist oral anticoagulant (NOAC) had an annualized rate of first recurrence of ischemic or hemorrhagic stroke or systemic embolism of 5.1% compared with 4.8% for aspirin (HR 1.07; 95% CI 0.87-1.33, P=0.52).
Recurrent ischemic stroke occurred at an identical 4.7% per year in both groups, Robert Hart, MD, of the Population Health Research Institute in Hamilton, Ontario, and colleagues reported online in the New England Journal of Medicine in a study published simultaneously with presentation at the European Stroke Organisation Conference in Gothenburg, Sweden.
Rivaroxaban substantially increased major bleeding, though, at an annualized rate of 1.8% compared with 0.7% on aspirin (HR 2.72, 95% CI 1.68-4.39, P<0.001). Life-threatening or fatal bleeding (HR 2.34), symptomatic intracranial hemorrhage (HR 4.02), and clinically relevant nonmajor bleeding (HR 1.51) were also significantly worse with rivaroxaban.
The trial included 7,213 patients ages 50 and older with "embolic stroke of undetermined source" -- i.e., not associated with proximal arterial stenosis or a recognized cardioembolic source, such as atrial fibrillation or left ventricular thrombus, and that are not lacunar -- who were randomized to 15-mg immediate-release rivaroxaban or 100-mg aspirin enteric coated tablets along with placebo given both groups to maintain blinding.
All participants had at least 20 total hours of cardiac rhythm monitoring to rule out atrial fibrillation lasting 6 minutes or longer.
"Rivaroxaban, including the 15-mg daily dose that was used in the current trial, has been effective for the prevention of recurrent stroke in patients with atrial fibrillation," the researchers noted, "and the absence of an observed lower rate of recurrent ischemic stroke with rivaroxaban than with aspirin in the current trial suggests that undetected paroxysmal atrial fibrillation was not a major cause of recurrent stroke."
While 7% of the included patients had a patent foramen ovale, the outcome influence of including these patients "is uncertain," according to the researchers, noting that the trials showing a benefit to closure in cryptogenic stroke came out just when recruitment stopped in NAVIGATE ESUS.
The trial was stopped early for excess bleeding risk without an offsetting chance of stroke prevention efficacy after patients had been followed for a median 11 months and 74% of the planned efficacy events had occurred.
Using a 20 mg rather than 15 mg dose of rivaroxaban wouldn't likely have made any difference in the findings, Hart's group suggested. But they noted that ongoing randomized trials are comparing other NOACs with aspirin in secondary prevention after cryptogenic stroke, such as RE-SPECT ESUS with dabigatran (Pradaxa) and ATTICUS with apixaban (Eliquis).

The trial was funded by Bayer and Janssen Research and Development.
Hart reported grants and personal fees from Bayer, outside of the NAVIGATE ESUS study.

• Primary Source

  New England Journal of Medicine

  Source Reference: Hart RG, et al "Rivaroxaban for stroke prevention after embolic stroke of undetermined source" N Engl J Med 2018; DOI: 10.1056/NEJMoa1802686.

Low-Dose Rivaroxaban Green-Lighted by FDA

At first I wouldn't have gone on this because of a lack of a reversal agent but since Dec. 2015 Praxbind (idrucizumab) is approved.
https://www.medpagetoday.com/Cardiology/VenousThrombosis/68882?

For continued prevention of recurrent VT

• by Nicole Lou, Contributing Writer, MedPage Today October 30, 2017

The FDA approved the 10 mg once-daily dose of rivaroxaban (Xarelto) for patients who have taken at least 6 months of anticoagulation, manufacturer Janssen announced.
Approval was based on the EINSTEIN CHOICE study in which both 20-mg and 10-mg doses of rivaroxaban beat aspirin in reducing a patient's risk of recurrent venous thromboembolism (VTE) -- by 66% and 74%, respectively -- without an elevated bleeding risk.
The 3,396-patient trial was presented as a late-breaker at the American College of Cardiology meeting this year. "This is a useful and safe clinical pathway for managing these patients," the presenter said at the time. There is "really no role for aspirin in this setting ... I hope these findings will encourage more physicians to prescribe rivaroxaban for these patients."
Rivaroxaban is to be prescribed at 15 mg twice daily in the first 21 days after a VTE occurrence, followed by 20 mg once daily up to the 6-month mark. With this new approval, physicians can then start patients on a 10 mg once-daily regimen if they are at continued risk for deep vein thrombosis and pulmonary embolism.
Recurrent VTE is a quality marker used by Medicare.

Rivaroxaban (Xarelto) flopped for preventing recurrent strokes and increased bleeding compared with aspirin in top-line results from the phase III NAVIGATE ESUS trial

Well, what is your doctor going to do with this information?  S/he should be able to point to a stroke prevention protocol that top neurologists have written. Unless you think YOUR doctor is tops in the field and has figured out what the answer is.  Guidelines are not good enough, demand a protocol.
Rivaroxaban (Xarelto) flopped for preventing recurrent strokes and increased bleeding compared with aspirin in top-line results from the phase III NAVIGATE ESUS trial
https://www.genengnews.com/gen-news-highlights/xarelto-fails-phase-iii-trial-in-esus/81255021

• Alex Philippidis

• Bayer and Johnson & Johnson’s Janssen Research & Development have acknowledged that their Xarelto^® (rivaroxaban) has failed a Phase III trial assessing the blockbuster anticoagulant in patients with a recent embolic stroke of undetermined source (ESUS).
  The companies said the Phase III NAVIGATE ESUS missed its primary efficacy endpoint of superiority over aspirin in reducing the risk of stroke (ischemic, hemorrhagic, and undefined stroke; transient ischemic attack with positive neuroimaging) and systemic embolism.
  NAVIGATE ESUS was halted early at the recommendation of the study’s Independent Data Monitoring Committee, after a planned interim analysis showed comparable efficacy between patients treated with Xarelto and those treated with aspirin for secondary prevention of stroke and systemic embolism.
  The analysis also concluded that Xarelto stood “little chance” of showing overall benefit if the study were completed, Bayer and Janssen added in separate statements.
  “Patients with ESUS currently have limited treatment options, and the role of anticoagulants in this area remains uncertain. We will now analyze the data from NAVIGATE ESUS to better understand this outcome and its implications,” Joerg Moeller, M.D., member of the executive committee of Bayer's Pharmaceutical Division and head of development, said in a statement.
  He added that patients will be contacted by their physician to switch to aspirin—and that clinical development of Xarelto would continue: “We are committed to continuing the extensive investigation of rivaroxaban for patients at risk of deadly blood clots.”
  The Phase III NAVIGATE ESUS study enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to either rivaroxaban 15 mg once daily or aspirin 100 mg once daily alone.
  The study’s primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis. Bleeding rates were “very low overall and within the expected range,” Janssen said, though both companies acknowledged that increased bleeding was observed in the rivaroxaban arm compared to the low-dose aspirin arm.
  Bayer and Janssen said a complete data analysis is expected to be presented in 2018, at an unspecified upcoming medical meeting.
  

Rivaroxaban Plus Aspirin More Effective Than Aspirin Alone for Secondary Cardiovascular Prevention

How up-to-date is your doctor and when will you be told about this? You'll have to decide if the risk of bleeding is worse than the risk of death
http://dgnews.docguide.com/rivaroxaban-plus-aspirin-more-effective-aspirin-alone-secondary-cardiovascular-prevention?overlay=2&

August 30, 2017

By Walter Alexander
BARCELONA, Spain -- August 30, 2017 -- After 1 year, the majority of patients with cardiovascular disease (CVD) who were given twice-daily rivaroxaban 2.5 mg plus daily aspirin reduced their risk of cardiovascular death, stroke, and myocardial infarction (MI), compared with patients who only received daily aspirin.
However, the combination therapy was associated with higher rates of major bleeding, reported John Eikelboom, MD, McMaster University, Hamilton, Ontario, and colleagues at the 2017 Annual Meeting of the European Society of Cardiology (ESC).
In the COMPASS study, patients (n = 27,395) with CVD from 33 countries were randomised 1:1:1 to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or standard therapy with aspirin 100 mg once daily.
The primary endpoint was a composite of cardiovascular death, stroke, and MI.
Clear superiority of the arm receiving rivaroxaban plus aspirin at interim analysis led the Data Safety Monitoring Board (DSMB) to recommend cessation of treatment in both monotherapy arms.
The primary endpoint was experienced by 4.1%, 4.9%, and 5.4% of patients in the combination, rivaroxaban alone, and aspirin alone arms, respectively. The hazard ratio (HR) for the rivaroxaban/aspirin versus aspirin arm was 0.76 (P< .0001). The rivaroxaban versus aspirin arm comparison showed no differences (HR = 0.90; P = .12).
Major bleeding rates were 3.1%, 2.8%, and 1.9%, respectively, with significant increases for both rivaroxaban-containing arms versus aspirin (P< .0001).
Net clinical benefit analysis taking into account primary and severe bleeding events found a significantly lower rate for the combination arm (4.7% vs 5.9%; HR = 0.80; P = .0005).
“The substantial benefits seen with rivaroxaban and aspirin support the approach of using low doses of the 2 treatments in combination,” said Dr. Eikelboom. “Recent trials in other disease areas have demonstrated substantial benefits from using low doses of a combination of drugs, and this concept is now further supported by the results of COMPASS.”
“Many of these bleeds were not serious and despite the increase in bleeding the results clearly show a net benefit for patients, as highlighted by an 18% reduction in mortality,” added co-author Stuart Connolly, McMaster University.
[Presentation title: Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease]

Some Blood Thinners May Increase Heart Attack Risk

Be careful out there. Hopefully your doctor has informed you of these risks. 

Some Blood Thinners May Increase Heart Attack Risk

A new study has examined whether different blood thinning medications prescribed to prevent strokes in patients with atrial fibrillation might increase the risk of heart attacks.

In the retrospective study of 30,146 patients, investigators found a twofold increased risk in patients taking direct acting oral anticoagulants (dabigatran and rivaroxaban) compared with those taking vitamin k antagonists such as warfarin. Heart attack risk was also higher in patients taking aspirin than in those taking warfarin.
"More research should be on-going as use of direct acting oral anticoagulants increases in the population," wrote the authors of the British Journal of Clinical Pharmacology study.
http://newsroom.wiley.com/press-release/british-journal-clinical-pharmacology/some-blood-thinners-may-increase-heart-attack-ri

• Full bibliographic informationBibliography
  Leo M Stolk MSc PharmD PhD, Frank de Vries PharmD PhD, Chiel Ebbelaar MSc, Anthonius de Boer MD PhD (3), Tom Schalekamp PhD, Patrick Souverein PhD,, Arina ten Cate-Hoek MD PhD, Andrea M Burden PhD. . Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants. British Journal of Clinical Pharmacology. DOI: 10.1111/bcp.13264.
  

Stroke Prevention for Patients With Atrial Fibrillation Similar With Warfarin, Newer Oral Anticoagulants

Didn't answer the outstanding question that there is no reversal agent for the newer ones. How many died or had negative outcomes because of no reversal agent? Can't these people even think of the correct questions to answer while doing research? Must I do everything? Think and wipe their ass? 

Stroke Prevention for Patients With Atrial Fibrillation Similar With Warfarin, Newer Oral Anticoagulants

An observational study comparing new oral anticoagulants with warfarin found stroke prevention to be similar, but the newer anticoagulants provided reduced intracranial bleeding, according to a study presented here at the 2016 Annual Meeting of the European Society of Cardiology (ESC).
The study included 43,299 patients with atrial fibrillation who were recruited from Danish nationwide administrative registries. In the cohort, 42% of patients were taking warfarin, 29% were taking dabigatran, 16% were on apixaban, and 13% were taking rivaroxaban.
“There has been a need to investigate safety and effectiveness of new oral anticoagulants versus warfarin in a ‘real world’ population and our Danish registries provide this opportunity,” said Laila Staerk, MD, Herlev and Gentofte University Hospitals, Herlev, Denmark.
Efficacy outcomes were stroke and all-cause mortality. Patients were followed until outcome, death, switch or discontinuation of initiated anticoagulant treatment, emigration, or study end.
During treatment, stroke occurred in 1,850 (4%) patients and there were 6,477 (15%) deaths.
The absolute stroke risk at 1 year of initiating treatment was similar for each of the 4 groups, at 2.01% for warfarin, 2.12% for dabigatran, 2.06% for rivaroxaban, and 2.46% for apixaban.
Absolute risk of all-cause mortality at 1 year after initiation of warfarin was 18.0%, dabigatran 11.5%, rivaroxaban 14.7%, and apixaban 14.9%.
Standardised absolute risk of intracranial bleeding at 1 year was reduced in patients who were taking the newer oral anticoagulants. Absolute risk was 0.60% for warfarin, 0.26% for dabigatran (P =0.05 vs warfarin), 0.47% for rivaroxaban, and 0.40% for apixaban (P = .05 vs warfarin).
“Among patients with atrial fibrillation who were new users of oral anticoagulation, while treatment with [these newer drugs] was not associated with a significantly lower risk of stroke, treatment with dabigatran and apixaban was associated with a significantly lower risk of intracranial bleeding compared with warfarin,” said Dr. Staerk.
[Presentation title: Stroke and All-Cause Mortality With Non-Vitamin K Antagonist Oral Anticoagulation Versus Warfarin in Atrial Fibrillation: a Nationwide Study. Abstract 1875]

FDA Delays Approval Of First Agent To Reverse Effect Of New Anticoagulants

A friend of mine refused to go on the new anticoagulants because of the lack of a reversal drug. I guess waiting even longer will need to happen.  Be careful out there.
http://cardiobrief.org/2016/08/17/fda-delays-approval-of-first-agent-to-reverse-effect-of-new-anticoagulants/

Risk Of Stroke High When Anti-Clotting Drugs Stopped

Make sure you fully discuss this with your doctors before stopping.
http://www.medicalnewstoday.com/releases/244610.php
Some patients with irregular heartbeats who are taken off anti-clotting medication face a high risk of stroke or blood clotting within a month, according to new research presented at the American Heart Association's Emerging Science Series webinar.

Patients with certain types of atrial fibrillation, or irregular heartbeat, take these drugs to reduce the risks of clots that could lead to a stroke. Sometimes they are instructed to stop taking the medication temporarily before surgery or permanently because of side effects.

"No matter what drug they are on, patients who need anticoagulation revert back to their intrinsic risk of stroke and embolism after discontinuation, so it shouldn't be done lightly," said Manesh Patel, M.D., lead author and assistant professor of medicine at the Duke University School of Medicine. "Unfortunately, it's unclear how to provide optimal anti-coagulation coverage during periods of transition."

Researchers analyzed data from a clinical trial known as ROCKET AF, finding the risk is similar whether patients are taking the drug warfarin or the newer anticoagulant rivaroxaban. Rivaroxaban is taken once daily and doesn't require the frequent monitoring of warfarin, which requires frequent dose-adjustment.

In ROCKET AF, rivaroxaban was found to be as effective as warfarin in preventing stroke and blood clots in more than 14,000 patients with atrial fibrillation. Patients also had no greater risk of bleeding. However, concerns persisted about possible increased rates of stroke and blood clots after discontinuing rivaroxaban, which led to a warning in the prescribing information.

Because of these concerns, the researchers analyzed strokes and blood clots that occurred following temporary interruptions, and between 3 and 30 days after early drug discontinuation or the transition to warfarin at the study's end.

Strokes and blood clots occurred:

• At similar rates with both drugs after a temporary interruption - 6.20/100 patient-years for those on rivaroxaban vs. 5.05/100 patient-years for those taking warfarin;
• At similar rates in both drugs after permanently stopping the medicines - 25.60/100 patient-years for people taking rivaroxaban (vs. 23.38/100 patient-years for those on warfarin;
• More often in the transition from rivaroxaban to open label therapy (6.42/100 patient-years) vs. warfarin (1.73/100 patient-years). However, the risk seems to be high only for stroke. There was no difference between the drugs when investigators evaluated all blood clot-related events (including strokes, heart attack and vascular death) within 30 days of stopping medication.