ENGAGE AF TIMI-48 study: new results for edoxaban


Results from the phase 3 ENGAGE AF-TIMI 48 study were announced at the American Heart Association (AHA) Scientific Sessions in Dallas. It found that the investigational, oral, once-daily direct factor Xa-inhibitor edoxaban, evaluated in two treatment arms (60mg and 30mg), achieved the primary endpoint of non-inferior efficacy versus warfarin in the prevention of stroke or systemic embolism (SEE) in patients with non-valvular atrial fibrillation (NVAF).
ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation) was a three-arm, randomised, double-blind, double-dummy, global phase 3 clinical trial comparing once-daily edoxaban with warfarin in 21,105 patients with NVAF at moderate-to-high risk of thromboembolic events at 1,393 centers in 46 countries.
Once-daily edoxaban demonstrated significant reductions in major bleeding compared to warfarin, achieving superiority for the principal safety endpoint. Results were also published online in the New England Journal of Medicine.
ENGAGE AF-TIMI 48 compared two edoxaban treatment arms, 60mg and 30mg, with warfarin for a median of 2.8 years. This represents the largest and longest trial with a novel anticoagulant in patients with atrial fibrillation performed to date. The edoxaban 60mg treatment arm had an annual incidence of stroke or SEE of 1.18% versus 1.50% for warfarin, and significantly reduced major bleeding by 20% (2.75% versus 3.43% per year, respectively).
The edoxaban 30mg treatment arm had an annual incidence of stroke or SEE of 1.61% versus 1.50% for warfarin, and significantly reduced major bleeding by 53% (1.61% versus 3.43% per year, respectively).
Patient-specific dosing was applied according to the study protocol. In both edoxaban treatment arms, the edoxaban dose was halved for patients with clinical factors that were known to increase the risk of bleeding (renal impairment, low body weight or concomitant use of certain P-glycoprotein inhibitors).
Patients receiving a reduced edoxaban dose in the 60mg treatment arm had an annual incidence of stroke or SEE of 2.32% versus 2.68% for warfarin and a significantly reduced major bleeding incidence of 3.05% versus 4.85%.
Patients receiving a reduced edoxaban dose in the 30mg treatment arm had an annual incidence of stroke or SEE of 3.14% versus 2.68% for warfarin and a significantly reduced major bleeding incidence of 1.50% versus 4.85%.
Robert Giugliano, senior investigator with the TIMI Study Group, Physician Cardiovascular Medicine, Brigham and Women’s Hospital, Associate Professor of Medicine, Harvard Medical School, and Co-Global Lead Investigator of the ENGAGE AF-TIMI 48 trial, said: “The results from the ENGAGE AF-TIMI 48 trial showed that edoxaban may provide a new treatment option for the prevention of stroke or systemic embolic events that demonstrates comparable efficacy to warfarin, while significantly reducing the risk of major bleeding.”
Professor John Camm, Professor of Clinical Cardiology, St George’s Healthcare Trust, said: “In the ENGAGE-AF Trial (TIMI48) the high dose strategy (60mg once daily with a reduction to 30mg daily in selected patients at randomisation or during the on-going trial) proved non-inferior to warfarin for the prevention of stroke and systemic embolus whilst at the same time significantly reducing major bleeding, intra-cranial haemorrhage and important composite endpoints representing an improved “net clinical benefit”. This is a new and potentially valuable clinical profile for a once daily non-VKA oral anticoagulant.”
The edoxaban clinical trial program, the largest in the history of Daiichi Sankyo, has now yielded positive data for edoxaban in two major diseases, stroke prevention in atrial fibrillation and treatment of acute venous thromboembolism.

Hemorrhagic stroke
The annual incidence of hemorrhagic stroke was 0.47% for warfarin compared to 0.26% for edoxaban 60mg and 0.16% for edoxaban 30mg. The annual incidence of ischaemic stroke was 1.25% for warfarin compared to 1.25% in the edoxaban 60mg treatment arm and 1.77% per year for the edoxaban 30mg treatment arm.

Intracranial hemorrhage
The annual incidence of intracranial hemorrhage was 0.39% for patients in the edoxaban 60mg treatment arm and 0.26% for the edoxaban 30mg treatment arm compared to 0.85% for warfarin. Fatal bleeds occurred at an annual rate of 0.21% in the edoxaban 60mg treatment arm and 0.13% for the edoxaban 30mg treatment arm compared to 0.38% for warfarin.

Stroke, SEE and cardiovascular death
Annualised rates for the key secondary composite endpoint of stroke, SEE and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban 60mg (p=0.005) and 4.23% with edoxaban 30mg (p=0.32). Edoxaban was also associated with reduced annualised cardiovascular mortality rates versus warfarin: the incidence was 3.17% for warfarin, 2.74% (p=0.013) for the edoxaban 60mg treatment arm and 2.71% (p=0.008) for the edoxaban 30mg treatment arm. The primary net clinical outcome (defined in the study protocol as the composite of death, stroke, SEE or major bleeding) was 8.11% per year for warfarin, 7.26% per year for the edoxaban 60mg treatment arm (p=0.003) and 6.79% per year for the edoxaban 30mg treatment arm (p<0.001).


Dabigatran safety data
Results from a new, long-term, combined analysis of the phase III RE-LY trial and its extension safety study RELY-ABLE were presented recently at the AHA.
Dabigatran etexilate was the first oral anticoagulant (OAC) approved by the US Food and Drug Administration in more than 50 years to reduce the risk of stroke and systemic embolism in patients with NVAF.
The efficacy and safety of dabigatran etexilate was established in the RE-LY trial, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF. RE-LY was a global, phase III, randomised trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as open label warfarin—INR 2.0–3.0—for stroke prevention.
Patients with NVAF and at least one other risk factor for stroke (i.e, previous ischaemic stroke, transient ischaemic attack, or systemic embolism, left ventricular ejection fraction <40 percent, symptomatic heart failure, New York Heart Association Class ≥2, age ≥75 years, age ≥65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years with a minimum follow-up period of one year.
The data showed that after a median follow-up of 4.6 years, with some patients followed up to 6.7 years, rates of stroke/systemic embolism and major bleeding were consistent with rates in previously reported analyses of RE-LY, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF.
Michael D Ezekowitz, Professor of Medicine at Thomas Jefferson Medical College in Philadelphia, said: “This is the first set of data to provide results after long-term continuous follow-up of more than four years in a large set of NVAF patients who were treated with one of the newer OACs. Patients with NVAF need long-term treatment with anticoagulants in order to lower their risk of stroke, and these data are crucial in understanding dabigatran etexilate’s long-term safety in patients with NVAF.”
Following the RE-LY trial, a total of 5,851 patients, who were randomised to either 110mg or 150mg twice daily (BID) of dabigatran, continued the same blinded dose of dabigatran in RELY-ABLE. Median follow up was 4.6 years, with a maximum 6.7 years total follow up (RE-LY plus RELY-ABLE).
This new analysis showed that the rates of stroke or systemic embolism for dabigatran 150mg BID and 110mg BID were 1.25% and 1.54% per year, respectively. The low rates of haemorrhagic stroke seen during RE-LY (approximately one case per thousand per year) were observed over the whole duration of follow-up.
Mortality rates were similar for the two dabigatran doses: 3.43% per year for 150mg BID and 3.55% per year for 110mg BID; HR 0.97 (95% CI: 0.87-1.08). Additional results from the combined analysis of RE-LY and RELY-ABLE found that rates of ischaemic stroke for dabigatran 150mg BID and 110mg BID were 1.03% and 1.29% per year, respectively.
Rates of major haemorrhage for dabigatran 150mg BID and 110mg BID were 3.34% and 2.76% per year, respectively.


Ex-smokers reduce heart risk more than previously estimated
Cigarette smokers who are over 65 years of age may be able to lower their risk of cardiovascular disease-related deaths to the level of never-smokers when they quit faster than previously reported, according to research presented at the AHA.
A study showed that older people who smoked less than 32 “pack years”—3.2 packs (20 cigarettes per pack) a day for no more than 10 years or less than one pack a day for 30 years—and gave up smoking 15 or fewer years ago lowered their risks of developing heart failure or dying from heart failure, heart attacks and strokes to the same level as those who had never smoked.
Previous research showed it may take up to 15 years of abstinence for smokers to reach similar cardiovascular death risks as people who never smoke. But many of the people in the study were able to reduce their risk in less than 15 years (median eight years).
Ali Ahmed, senior researcher and professor of cardiovascular disease at the University of Alabama at Birmingham’s School of Medicine, said: “Now there’s a chance for even less of a waiting period to get a cleaner bill of cardiovascular health. Smoking is the most preventable cause of early death in America—if you smoke, quit and quit early.”
Ahmed and his colleagues analysed 13 years of medical information compiled in the Cardiovascular Health Study, started in 1989 and funded by the National Heart, Lung, and Blood Institute. They compared 853 people who quit smoking 15 or fewer years before with 2,557 people who had never smoked.
Of the 853 former smokers, 319 had smoked less than 32 pack years. Pack years are determined by multiplying the cigarette packs smoked per day times the number of years a person has smoked. All participants were over age 65 years of age. Results were adjusted for age, gender and race.
Smokers who smoked less than 32 pack years but quit up to 15 or more years ago still had higher risks of dying from causes unrelated to cardiovascular health, such as cancer, chronic obstructive pulmonary disease and emphysema. Former smokers who smoked more than 32 pack years had higher risks of dying from any health condition.


Warning signs for sudden cardiac death
Sudden cardiac arrest isn’t always so sudden, according to research presented at the AHA.
In a study of middle-age men in Portland, Oregon, more than half had possible warning signs up to a month before their hearts stopped abruptly. About 360,000 out-of-hospital cardiac arrests are reported each year in the US, according to the AHA. Only 9.5% of people who suffer a cardiac arrest outside the hospital survive.
The new research is part of the 11-year-old Oregon Sudden Unexpected Death Study, which involves one million people in the Portland metro area. Researchers gathered information about the symptoms and health history of men 35 to 65 years old who had out-of-hospital cardiac arrests in 2002–12.
Among 567 men who had out-of-hospital cardiac arrests, 53% had symptoms prior to the cardiac arrest. Of those with symptoms, 56% had chest pain, 13% had shortness of breath and 4% had dizziness, fainting or palpitations. Almost 80% of the symptoms occurred between four weeks and one hour before the sudden cardiac arrest.
Most men had coronary artery disease, but only about half had been tested for it before their cardiac arrest.
Researchers are conducting similar work in women.