• DOUBLE BLIND, DOUBLE DUMMY, SUPERIORITY TRIAL COMPARING APIXABAN AND ASA
• PATIENTS WITH NON VALVULAR AF AND AT LEAST ONE RISK FACTOR FOR STROKE WHO HAD FAILED OR WERE UNSUITABLE FOR VKA THERAPY
• AP 5 MG BID (N 2808)
• ASA 81 TO 324 (N =2791)

• DOUBLE BLIND, DOUBLE DUMMY, NONINFERIORITY TRIAL COMPARING APIXABAN AND WARFARIN
• PATIENTS WITH NVAF AND AT LEAST ONE RISK FACTOR FOR STROKE
• AP 5 BID (n= 9120)
• warf titrated to inr of 2.0 to 3.0 (n 9081)

• both nvaf with one additional risk factor for stroke, however in averroes the patients had either failed prior warf thearpy or were considered unsuitable for warf therapy
• asa comparator in averroes vs warf in aristotle.

• AVERROES SUPERIORITY TRIAL VS ARISTOTLE  TO CONTROL THE OVERALL TYPE I ERROR, PRESPECIFIED HIERARCHIAL SEQUENTIAL TESTING WAS PERFORMED FIRST ON THE PRIMARY OUTCOME FOR NONINFERIORITY, THEN ON THE PRIMARY OUTCOME FOR SUPERIORITY, THEN ON MAJOR BLEEDING AND FINALLY ON DEATH FROM ANY CAUSE.

• based on ISTH
• MAJOR BLEEDING IS:
• DECREASE IN HEMOGLOBIN OF ≥2 G/DL ORVER A 24 HR PERIOD
• TRANSFUSION OF ≥2 UNITS OF PACKED RED BLOOD CELLS
• BLEEDING THAT OCCURS INTO A CRITIAL SITE (intracranial intraspinal, intraocular, percardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal)
• bleeding that is fatal

• dose was 5 mg in both unless patients were expected to have a higher exposure to apixaban. which were identified by the following characteristics.
• age ≥80 years
• body weight ≤60 kg
• serum creatinine level ≥ 1.5 mg/dl 
• primary efficacy endpoint the same
• safety endpoints: the primary safety endpoint was the same: the occurrence of major bleeding; clinically relevant non major bleeding and minor bleeding were also safety endpoints.

• 12TH CENTURY PHILOSOPHER/SCIENTIST AVERROES WHO HAD A SPECIAL INTEREST IN MEDICINE
• THE FIRST TO PROPOSE A CARDIAC/VASCULAR ORIGIN FOR STROKE.

• RANDOMIZED
• ACTIVE-CONTROLLED
• DOUBLE BLIND
• DOUBLE DUMMY
• SUPERIORITY
• PATIENTS W/ NVAF AND 1 OTHER RISK FACTOR FOR STOKE AND HAD FAILED OR WERE UNSUITABLE FOR WARF THERAPY
• n = 5599
• PATIENTS FIRST ENTERED A SCREENING PHASE OF 0-28 DAYS.
• FOLLOW UP AT 1 MO THEN 3 MO THEN EVERY 3 MO UNTIL COMPLETION.

• AGE ≥50
• PERMANENT, PERSISTENT OR PARAXYSMAL AF DOCUMENTED BY 12 LEAD ECG ON THE DAY OF SCREENIN; OR IF NOT IN AF AT SCREENING, AF MUST BE DOCUMENTED IN THE 6 MO BEFORE ENROLLMENT
• AT LEAST ONE OF THE FOLLOWING RISK FACTORS:
• prior stroke or tia
• age ≥75
• arterial hypertension on treatment
• diabetes mellitus
• heart failure (NYHA class ≥2 at time of enrollment) or LVEF ≤35%.
• documented pad
• not currently receiving VKA therapy.

• AF due to reversible causes
• valvular disease requiring surgery
• planned af ablation procedure within 3 mo
• conditions other than AF that require chronic anticoagulation
• current alcohol or drug abuse or psychological reasons taht make study participation impractical
• patients with serious bleeding in the last 6 mo or at high risk of bleeding
• severe co-morbid condition with life expectancy <1 year
• ALT or AST >2 x ULN or a total bilirubin > 1.5 x ULN.
• allergy to asa
• use of an investigational drug or device within 30 days or prior randomization into an apixaban clinical study
• prisoners or subjects who are compulsorily detained
• women who are pregnant, breast feeding or of child bearing potential who are unwilling to meet the study requirements for pregnancy testing or unwilling or unable to use an acceptable method to avoid pregnancy.
• use of a prhibited or estricted treatment at entry.

• age - 70
• chads2 - 2.0
• 52% permanent af
• 40% CHF (33% CHF (class 1 or 2))
• 19% diabetes
• 86% hypertension
• 14% prior stroke
• LVH 17%
• 68% AF

CONCURRENT MEDS

• patients taking plavix or ticlid were not elegible, however if patients developed an indication for dual anti platelet therapy they could take asa <100 and plavix.
• potent inhibitors of p-450 enzyme 3a4 such as azoles, macrolides, and protease inhibitors)
• antithrombotic agents other than asa and plavix

• efficacy - stroke (ischemic or hemorrhagic) or systemic embolism
• safety - major bleeding
• other - MI, vascular death, all cause death, composites of major vascular events and net clinical benefit.

• event driven so duration depended on the time required to accrue the primary outcome events.
• designed to continue until there were 226 subjects with stroke/systemic emboli and to ahve at least a 90% power to detect a 35% RRR.
• superiority

• 43% physician determined INR's could not be obtained as required
• 21% risk of stroke only moderate (chads2 score of 1)
• 37% patients did not want to take VKA therapy.

• stopped early
• 1.6% per year apx and 3.7% asa HR .45
• 55% RRR
• secondary outcomes
• composite stroke systemic embolism, MI or vasc death RRR = 34% vs asa.

• percent per year of major bleeding was not significantly different.
• 1.4% vs. 1.2% asa.

• at 2 years, 17.9%abx vs 20.5% asa

• Signficantly fewer patients had serious ae with abx - 22% vs 27%
• due primarily to lower number of events related to vascular disorders of teh CNS in apx group.

• results consistent across subgroups

• RANDOMIZED
• ACTIVE-CONTROLLED,
• DOUBLE BLIND
• DOUBLE DUMMY
• NON INFERIORITY
• INCLUDED WARF PATIENTS GOAL WAS TO HAVE 40% WARF NAIVE.

number of patients & dosing considerations for aristotle

• 18,201
• same as averroes in terms of dosing
• 5mg bid or 2.5 if  (patients had at least 2 of ≥80 years, body weight ≤60 kg or creatinine ≥1.5. + warf placebo.
• vs warf target INR 2 - 3 + abx placebo

• Aged ≥18 years
• Permanent, Persistant, AF or atrial flutter on ECG at enrollment, or AF or atrial flutter documented b ECG or as an episode ≥1 min on thythm strip. Holter monitor or intracardiac recording on 2 separate occasions at least 2 wk apart in the 12 mo before enrollment.
• at least one of the following risk factors for stroke:
• aged ≥75
• prior stroke tia, or systemic emboli
• symptomatic CHF w/in  3 mo or LVEF ≤40%
• diabetes
• hypertension requiring pharm. treatment
• women of childbearing potential must use contraception to avoid pregnancy during treatment period or for 2 wk after last dose of study medications whichever is longer

see module for complete list:

• af or flutter due to reversible cause
• increased bleeding risk believed to be a contraindication to oral anticoagulation
• planned major surgery
• require asa >165 mg/day
• severe renal insufficiency crcl <25ml/min

• death from any cause
• also: composite of stroke, systemic embolism, mi or death from any cause
• mi
• composite of stroke, systemic emboism, mi, or death fom any cause
• pulmonary embolism or dvt

• 2 groups were well matched
• median age 70
• mean chads2 score was 2.1
• 35.3% women
• approximately 57% had previously received VKA therapy
• 19% had had a previous stroke, tia or systemic embolism
• 25% had diabetes
• 35.5% had LVEF or HF

• fewer patients in apixaban group discontinued study drug compared to warf
• APX = 25.3% (3.6% due to death) vs. 27.5% (3.8% due to death)

Aristotle Results?

Primary Endpoint

• apx statistically superior to warf in the primary endpoint
• 212 or 1.27% per patient year vs. 265 patients in warf group (1.60% per patient year)
• 21% RRR

• 11% RRR
• 603 apx patients 3.52% vs. 669 patients warf 3.94%

• the relative risk of hemorrhagic stroke was 49% lower in the apx group vs. warf.
• the relative risk of ischemic stroke was 8% lower with apx compared with warf.

• major bleeding occured in signficantly fewer patients who received apx.
• 327 or 2.13% per year vs. 462 patients in the warf arm. 3.09% per year.
• 31% RRR
• apx significantly reduced the rrelative risk of intracranial bleeding by 58%
• apx produced less bleeding on all three scales (ISTH, GUSTO, and TIMI)

• SIMILAR BETWEEN 2 GROUPS:
• 81.5% APX vs. 83.1% warf
• serious ae:
• 35% APX vs. 36.5% warf
• serious ae reported in greater than 1% of either group:
• AF 3.3% apx vs. 3.2% warf.
• pneumonia 2.2% vs. 2.6%

• the reduction in the primary efficacy outcome with apx was generally consistent across most major subgroups and there were no significant interactions among groups.
• In terms of subgroup analysis for the primary safety outcomes, the only baseline characteristics for which the interaction was significant were diabetes and renal function. with a greater reduction in bleeding among patients who did not have diabetes and among patients with moderate or severe renal dysfunction.