AF

Trial Halted for Bleeding Reduction With Abelacimab vs Rivaroxaban in AF

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A phase 2 trial of the investigational factor XI inhibitor, abelacimab, in patients with atrial fibrillation (AF) who are at moderate to high risk for stroke has been stopped early due to “an overwhelming reduction” in the primary endpoint — major and clinically relevant nonmajor bleeding — in patients taking abelacimab vs those on rivaroxaban.

The announcement of topline results of the AZALEA-TIMI 71 trial was made by Anthos Therapeutics, the company developing abelacimab.

“The AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to the standard-of-care anticoagulant,” Marc Sabatine, MD, chair of cardiovascular medicine at Brigham and Women’s Hospital, and chair of the TIMI study group, stated in the Anthos press release.

“With a median of 21 months of follow-up, spanning more than 2,000 patient years, AZALEA-TIMI 71 represents a landmark study confirming the promise of Factor XI inhibition as causing substantially less bleeding than a current standard-of-care,” Sabatine added.

Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against factor XI and its active form, factor XIa. At the 150-mg dose given subcutaneously once monthly, the drug maintains around 98% inhibition of factor XI, in line with the benign bleeding profile of patients with genetic factor XI deficiency, the company notes.

The AZALEA-TIMI 71 study is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in 1287 patients with AF who are at moderate to high risk for stroke. Full results of the study will be presented at an upcoming scientific congress.

Patients in the rivaroxaban arm can transition to abelacimab in an extension study.

In a previous proof-of-concept study published in The New England Journal of Medicine in 2021, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism (VTE) vs enoxaparin in patients undergoing knee surgery.

A phase 3 trial in AF patients is now planned. The LILAC-TIMI 76 study is an event-driven, randomized trial to evaluate the efficacy and safety of abelacimab relative to placebo on the rate of ischemic stroke or systemic embolism in AF patients who have been deemed to be unsuitable for currently available anticoagulation therapy. Patients will be randomized to receive abelacimab 150 mg subcutaneously or matching placebo once monthly. The researchers aim to enroll approximately 1900 patients from North America, Europe, Latin America, the Middle East, and Asia.

Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said that, “Abelacimab embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions.”

It is estimated that 12.1 million people in the United States will have AF by 2030, but 40%-60% of patients with AF are not prescribed anticoagulants today, one of the main reasons being concerns about bleeding, the company notes.

“Abelacimab has the potential to provide a game-changing treatment option for all those patients who live with the daily fear of bleeding while taking current anticoagulants,” said Leslie Lake, president of the National Blood Clot Alliance, in a quote.

Abelacimab has been granted a fast-track designation by the US Food and Drug Administration for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Several other Factor XI inhibitors are in development and have also shown promising results in terms of a more benign bleeding profile than current standard-of-care anticoagulants.

Rivaroxaban superior to warfarin for stroke protection in real-world nonvalvular AF population

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In an observational study of real-world patients with nonvalvular atrial fibrillation, those treated with rivaroxaban had a significant risk reduction for severe stroke and all-cause mortality after stroke compared with patients who were prescribed warfarin, according to research published in Stroke.

In a retrospective cohort study of patients who began treatment with rivaroxaban (Xarelto, Janssen/Bayer) or warfarin within 30 days of nonvalvular AF diagnosis, researchers found that rivaroxaban reduced the risk for stroke by 19% (HR = 0.81; 95% CI, 0.73-0.91) compared with warfarin.

Moreover, analysis by stroke severity found that rivaroxaban provided a 48% risk reduction for severe stroke (NIH stroke scale score, 16 to 42; HR = 0.52; 95% CI, 0.33-0.82) and 19% for minor stroke (NIH stroke scale score, 1 to < 5; HR = 0.81; 95% CI, 0.68-0.96) compared with warfarin, but revealed no difference for moderate stroke (NIH stroke scale score, 5 to < 16; HR = 0.93; 95% CI, 0.78-1.1).

“This study showed risk reduction with rivaroxaban treatment in stroke overall and across all but the moderate stroke category,” Mark Alberts, MD, FAHA, chief of neurology at Hartford Hospital and physician-in-chief at Ayer Neuroscience Institute, Hartford, Connecticut, and colleagues wrote. “A possible explanation for the nonsignificant risk reduction for moderate stroke is insufficient power, given that the occurrence of stroke is so rare in this study population of patients with nonvalvular AF taking anticoagulants.”

In other findings, patients with nonvalvular AF who were treated with rivaroxaban experienced a risk reduction for all-cause mortality of 24% poststroke (HR = 0.76; 95% CI, 0.61-0.95) and 59% within 30 days (HR = 0.41; 95% CI, 0.28-0.6) compared with patients treated with warfarin.

For this retrospective cohort study, researchers included de-identified patients from the Optum Clinformatics Database who received rivaroxaban or warfarin within 30 days of initial diagnosis for nonvalvular AF. Before diagnosis, patients had 6 months of continuous health plan enrollment and a CHA2DS2-VASc score of at least 2.

“This study’s findings may help health care providers choose more effective treatments for managing their patients with nonvalvular AF, which may improve stroke prevention, optimize functional outcomes secondary to risk reduction of severe stroke and reduce mortality from stroke,” the researchers wrote. – byScott Buzby

Autoimmune disorders associated with AF risk

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Autoimmune disorders were associated with elevated atrial fibrillation risk, particularly in women, according to a study published in EP Europace.

Using UK Biobank data from 2006 to 2022, 494,072 patients without AF (median age, 58 years; 55% women) were analyzed for rheumatic fever, gastrointestinal (GI) autoimmune diseases, autoimmune diseases of the musculoskeletal system and connective tissues, and neurological autoimmune diseases. After a median of 12.8 years, 5.5% of patients were diagnosed with new-onset AF.

Atrial fibrillation smartphone
Autoimmune disorders were associated with elevated AF risk, particularly in women.
Source: Adobe Stock

“We found significant associations between new-onset AF and rheumatic fever without heart involvement, GI (Crohn’s disease and ulcerative colitis) and musculoskeletal system (rheumatoid arthritis, psoriatic and enteropathic arthropathies, polyarteritis nodosa, systemic lupus erythematosus and systemic sclerosis) autoimmune diseases, with AF incidence,” Martijn J Tilly, MS,of the department of epidemiology at Erasmus MC, University Medical Center Rotterdam, the Netherlands, and colleagues wrote. “Moreover, we found evidence of significant differences between men and women in these associations.”

The researchers found that patients had higher risk for developing AF if they had rheumatic fever without heart involvement (HR = 1.47; 95% CI, 1.26-1.72), Crohn’s disease (HR = 1.23; 95% CI, 1.05-1.45), ulcerative colitis (HR = 1.17; 95% CI, 1.06-1.31), rheumatoid arthritis (HR = 1.39; 95% CI, 1.28-1.51), polyarteritis nodosa (HR = 1.82; 95% CI, 1.04-3.09), systemic lupus erythematosus (HR = 1.82; 95% CI, 1.41-2.35) or systemic sclerosis (HR = 2.32; 95% CI, 1.57-3.44).

Women presented autoimmune disorders at higher rates than men for all but ulcerative colitis and ankylosing spondylitis. Rheumatic fever without heart involvement (HR = 1.79; 95% CI, 1.45-2.2), Crohn’s disease (HR = 1.35; 95% CI, 1.05-1.73), musculoskeletal system disorders (HR = 1.51; 95% CI, 1.38-1.66), rheumatoid arthritis (HR = 1.5; 95% CI, 1.35-1.67), psoriatic and enteropathic arthropathies (HR = 2.01; 95% CI, 1.32-3.05), systemic lupus erythematosus (HR = 1.79; 95% CI, 1.34-2.4), systemic sclerosis (HR = 2.51; 95% CI, 1.64-3.85), ankylosing spondylitis (HR = 1.53; 95% CI, 1.13-2.07) and multiple sclerosis (HR = 1.37; 95% CI, 1.07-1.75) were all significant associations for new-onset AF in women.

Although the incidence rate of new-onset AF in the total population was 4.49 per 1,000 person-years, the rate was 6.25 per 1,000 person years in men and 3.08 per 1,000 person-years in women.

“Autoimmune diseases are significantly associated with the risk of new-onset AF in this prospective population-based study, comprising almost half a million participants,” Tilly and colleagues wrote. “Our findings further elaborate on and contribute to the current knowledge of the pathophysiological differences in autoimmunity between men and women.”

Anti cougalant in atrial fibrillation.

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The Problem

An 82-year-old woman with hypertension and diabetes is seen in the clinic for newly diagnosed atrial fibrillation (AF). She uses a walker and fell twice last year. She completes activities of daily living (ADLs) independently. Should she be prescribed an anticoagulant?

AF markedly increases the risk of ischemic stroke, which often results in disability and threatens independence.1 Anticoagulants reduce stroke rates but simultaneously increase hemorrhage rates. Unfortunately, predictors of benefit and harm overlap considerably; for example, advanced age predicts both stroke and hemorrhage risk. Guidelines give clear-cut therapeutic recommendations based on stroke risk but provide less specific guidance on balancing the increased hemorrhage risk.2 Although risk models help quantify bleeding risk, the consequences of bleeding (e.g., disability) in older adults are ill defined. The result is a quagmire.

The Pros and Cons of Anticoagulant Use in Older Adults with AF

Randomized controlled trials (RCTs) unequivocally demonstrate that anticoagulants reduce stroke rates, including in older adults.3 We have long understood that anticoagulants also increase the risk of intracranial hemorrhage, which is uncommon but devastating. By comparison, many consider the more common extracranial hemorrhage (e.g., gastrointestinal hemorrhage) to be a temporary inconvenience. While this is likely true for younger adults, bleeding may be more consequential for older adults.

Stroke prevention is important because strokes often result in a sudden loss of ADL independence. Now consider that hospitalization for any reason poses a risk to older adults’ independence: one in three develop lasting hospital-acquired disability.4 Even when the underlying disease is treated, hospitalization of older adults may result in lost ADL independence. Given the typical management for hemorrhage (e.g., procedures, not allowing patients to eat), such admissions are bound to result in hospital-acquired disability. Although stroke-associated disability has been reported in RCTs, hemorrhage-associated disability has not been commonly reported.

Older also adults prize quality of life.5 Anticoagulants impose costs to quality of life not captured in RCTs, including so-called nuisance bleeding, delays for urgent procedures, physician visits, medication interactions, and out-of-pocket expenses. Such costs are particularly burdensome to vulnerable older adults. They are hardly a niche population: 80% of older adults with AF are vulnerable with one or more geriatric syndromes (e.g., falls, frailty).6

What We Know

Guidelines recommend using the CHA2DS2-VASc score to estimate stroke risk and offer anticoagulants above a certain threshold — one that nearly all older adults with AF surpass.2,6 The recommendation implies that above the threshold, the benefits outweigh the risks; however, this threshold has not yet been tested with regard to disability and quality of life.

Faced with uncertainty, anticoagulant use in older adults with AF is far below what the guidelines suggest: only 45% consistently use anticoagulants.7 When surveyed about the decision not to treat specific patients in their care, physicians cite frailty, falls, and life expectancy — geriatric features that are under-addressed in RCTs.8,9

The ELDER-AF trial addressed anticoagulant use in older adults with AF.10 The investigators randomly assigned adults 80 years of age or older who were not considered candidates for therapeutic anticoagulation to placebo or low-dose edoxaban, a direct-acting oral anticoagulant. The trial again demonstrated that anticoagulants reduce stroke risk by 66%.

The trial also underscored the trouble with anticoagulants in older adults. Major bleeding, the primary safety outcome, was not statistically higher with treatment. However, this outcome excludes clinically relevant nonmajor bleeding, which is common and consequential.11 Clinically relevant nonmajor bleeding includes hemorrhages requiring interventions like hospitalization, endoscopy, and surgery. Using this more germane end point, anticoagulation increased bleeding risk by 65%. In a trial in which one sixth of all participants had major or clinically relevant nonmajor bleeding, no data were presented on the outcomes of bleeding events. We are left wondering — did bleeding result in lost independence or decrements in quality of life?

What We Need

A trial that compares oral anticoagulants to placebo for older adults with AF where function and quality of life are the primary outcomes would capture the broader impact of therapy that many older adults prioritize. Such a trial would answer straightforward questions: If the 82-year-old woman described at the beginning of this article uses an anticoagulant, will it improve her chances of remaining ADL independent? Will it sustain her quality of life?

The work ahead is to co-design and execute a trial with stakeholders — older adults with AF, caregivers, and physicians — whose decisions we seek to inform. This trial would recruit a population similar to the ELDER-AF trial: older adults with AF for whom physicians have misgivings about anticoagulants or patients who, for any reason, decided not to use anticoagulants despite their physician’s recommendation. Based on projections from disability rates after stroke and hemorrhage, and studies of quality of life in AF,12,13 this trial would need to randomly assign approximately 1600 patients to treatment with 18 months of follow-up to detect a 5% absolute change in ADL independence and a 0.15-SD change in the 36-Item Short Form Health Survey physical component score. The results of such a trial could provide clarity for millions of older adults with AF and their physicians who, with current data, struggle to balance the benefits and harms of anticoagulants.

Rheumatoid Arthritis Linked to Risks for Atrial Fibrillation and Stroke.

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Close monitoring of RA patients is warranted.

Rheumatoid arthritis (RA) is associated with elevated risks for myocardial infarction and cardiovascular mortality (for example, JW Womens Health May 20 2003). To assess whether people with RA are at excess risks for atrial fibrillation (AF) and stroke, researchers analyzed data from 4.2 million people (age >15 years) in Denmark who were free of RA, AF, and stroke before 1997 (baseline).

During a median follow-up of 4.8 years, roughly 18,000 people developed RA (mean age at onset, 59), 156,000 developed AF, and 165,000 experienced stroke. The risk for AF, adjusted for age and sex, was nearly 40% higher among people with RA than in the rest of the population (8.2 vs. 6.0 events per 1000 person-years). Adjusted risk for stroke was more than 30% higher among people with RA than in the rest of the population (7.6 vs. 5.7 events per 1000 person-years).

Comment: In this population-based study, people who developed rheumatoid arthritis had significantly increased risks for atrial fibrillation and stroke. This finding is biologically plausible; for example, systemic inflammation is associated with both AF and stroke. The authors estimate that for every 12 patients followed for 10 years after RA diagnosis, 1 will develop AF. They therefore recommend closely monitoring RA patients for development of AF and adding RA as a factor in risk-stratification schemes for stroke.

Source:Journal Watch General Medicine