Leah SmithDuquesne University

Class of 2012 PharmD Candidate

Overview of Atrial Fibrillation and its current treatments

Comparison of warfarin and apixaban and their affect on the clotting cascade.

Population and methods Primary and Secondary outcomes, as well

as safety outcomes What does this mean for the future of

anticoagulation therapy.

•Published in the New England Journal of Medicine•Lead author Dr. Christopher Granger is the director of cardiac care at Duke University.•This was a worldwide study with a majority of the American physicians associated with Duke University Medical Center and the Duke Clinical Research Institute. •Article summarized results from the ARISTOTLE trial

•Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation.

•A majority of the funding came from Bristol-Myers Squibb and Pfizer.•Additional grants were mentioned from other pharmaceutical companies including: AstraZeneca, Novartis, GlaxoSmithKline, Johnson & Johnson, Merck, Bayer Healthcare, etc

•Trial designed by Bristol and Pfizer representative as well as academic investigators and was approved by the ethics committees of each of the 1034 investigational sites.

To compare apixaban with warfarin for the prevention of stroke or systemic embolism in patient with atrial fibrillation and at least one additional risk factor for stroke.

Primary purpose to establish non-inferiority to warfarin.

Epidemiology: AF is the most common sustained rhythm disturbance and is responsible for 1/3 of hospitalizations for arrhythmiasaccounts for more than 1.7 million

hospitalizations per year among Medicare patients.

Affects approximately 2.2 million adults The rate of incidence is expected to double each

year due to the aging population with over 50% of affected adults being 80 years or older.

DISEASEDEX™ Emergency Medicine Clinical ReviewCXMD Atrial Fibrillation

Definition: A supraventricular tachyarrhythmia resulting from uncoordinated electrical activity causing a mechanical malfunction of the atrial heart muscle.

Etiology: Any process that irritates, inflames, scars, or stretches the atrial muscles increase the possibility of fibrillation. A single point of repetitive rapid fire, most commonly from the pulmonary

vein, is the main cause of AF. 90% of AF rapid fire focus points are located in the left atrial muscle which

can extend up to 3 cm into the pulmonary veins. Most common causes of AF:

Increase atrial pressure due to high systemic or pulmonary hypertension. Atrial ischemia (CAD) Inflammatory atrial diseases: pericarditis, amyloidosis, etc Drugs: Alcohol and caffeine Endocrine disorders: Hyperthyroidism, Pheochromocytoma Postoperative procedures of the cardiothoracic or esophageal regions. Hemorrhagic or ischemic stroke.

DISEASEDEX™ Emergency Medicine Clinical ReviewCXMD Atrial Fibrillation

There are four identified patterns:◦ First detected AF: symptomatic or self-limited, paroxysmal or persistent. Two or more

episodes classify as recurrent. ◦ Paroxysmal AF: generally lasting 7 days or less with spontaneously termination. ◦ Persistent AF: longstanding (lasts longer than 7 days) with no spontaneous termination.

AF present more than a year is included. ◦ Permanent AF: persistent AF where an attempt at cardioversion cannot be attempted or

has failed. Symptom Class: after a pattern is identified they can be characterized by

symptom class. Class 0: completely asymptomatic Class 1: symptoms are minimal and do not affect quality of life. No syncope or heart failure

present. Class 2: In persistant/permanent mild awareness of symptoms. In paroxysmal, rare

episodes with mild symptoms experienced. Class 3: Consistent awareness of symptoms in persistant/permanent. In paroxysmal, more

frequent episodes with moderate to severe symptoms. Class 4: Highly symptomatic, severely affecting quality of life in all patterns. Syncope and

Heart Failure most likely present. Complications for patients with AF include:

◦ Congestive heart failure ◦ Thromboembolic stroke ◦ Arterial embolism ◦ Tachycardia-induced cardiomyopathy

DISEASEDEX™ Emergency Medicine Clinical ReviewCXMD Atrial Fibrillation

Three goals of AF treatment/management:◦ Ventricular rate control◦ Correcting any rhythm disturbance◦ Preventing Thromboembolism

Target therapeutic goals:◦ Resting HR: 60-80 bpm◦ Exercise HR: <100bpm on 6 minute walk◦ 24 hour average HR with Holter Monitor:

<100bpm◦ INR goal between 2 & 3.

CXMD Atrial Fibrillation

Rate Control◦ Beta-Blockers and Calcium-Channel Blockers are

considered equal in efficacy. BB: Metoprolol, Propranolol, Atenolol, Bisoprolol,

Carvedilol Do not use in patients with asthma, advanced heart

block, or acute heart failure. CCB: Diltiazem & Verapamil

Do not use in patient with left ventricular dysfunction and have drug interactions with CYP450 metabolized drugs.

◦ Digoxin and Amiodarone are considered second line agent unless CHF is present.

CXMD Atrial Fibrillation

Rhythm control◦ Normal Heart structure & Hypertension w/o LVH :

1st line: dronedarone, felcainide, propafenone, sotalol 2nd line: amiodarone, dofetilide

◦ Hypertension with LVH: 1st line: dronedarone, amiodarone.

◦ CAD 1st line: dofetilide, dronedarone, sotalol 2nd line: amiodarone

◦ Class I-II NYHA HF: 1st line: amiodarone, dofetilide, dronedarone

◦ Class III NYHA HF: 1st line: amiodarone, dofetilide

CXMD Atrial Fibrillation

Antithrombotic therapy is indicated in all patients (except first incidence Class 0) with AF in addition to anti-platelet or anticoagulant therapy.

The use of anti-platelet therapy over anticoagulation therapy is usually due to compliance issues or contraindications for anticoagulation treatment.

CXMD Atrial Fibrillation

Warfarin inhibits the production of vitamin K which intern inhibits the synthesis of vitamin K-dependent clotting factors (2, 7, 9 and 10)

Dosing: initial 2 to 5 mg QD◦ adjust dose based on INR◦ usual maintenance 2-10mg QD

Requires frequent INR testing (no less than every 4 weeks) and careful diet considerations with foods containing vitamin K.

Warfarin DRUGDEX

Has not yet been FDA approved. Oral direct factor Xa inhibitor.

◦ 12 hour half life.◦ 25% renal excretion.

AVERROES trial has already shown that apixaban in patients contraindicated for warfarin therapy apixaban, as compared to aspirin, reduces rate of stroke by 55% without increasing incidence of major bleeding.

Dosing is 5mg BID with a decrease to 2.5mg BID if the patient was 80 years of age or older, a body weight less than 60kg, and a SCr 1.5mg/dL or more.

No drug food interactions or consistent monitoring.

APIXIBANWARFARIN

Inclusion Criteria: Atrial fibrillation or flutter at time of

enrollment or 2 or more episodes of AF documented by ECG at least 2 weeks apart in the last year.

Prescence of atleast one of the following risk factors:◦ At least 75 years old◦ Previous stroke◦ Transient ischemic attack◦ Systemic embolism◦ Symptomatic HF with the past 3

months◦ Left ventricular ejection fraction of no

more than 40%◦ Diabetes◦ Hypertension requiring

pharmacologic agents.

Exclusion Criteria: AF due to a reversible causes Moderate to severe mitral stenosis Other conditions present that required

anticoagulation therapy. Stroke within the past 7 days A requirement of aspirin >165mg a

day or a requirement of both aspirin and clopidogrel.

Severe renal insufficiency (SCr >2.5mg/dL or CrCl <25ml/min)

Total patient enrollment: 18,201◦ 9120 assigned apixaban, 9081warfarin

A total of 1034 testing sites were used in 39 different countries.

Investigors tried to enroll >40% of patient population at each testing site who have were warfarin naïve. ◦ 57% of total population fell into this category

Patients were classified as not having received warfarin is they had not received any vitamin K antagonist for no more than 30 consecutive days.

•Primary Objective: to show non-infereriority of apixaban in comparison to warfarin for the prevention of stroke systemic embolism in patients with AF. •Secondary objectives: determine superiority of apixaban to warfarin with respect to the incidence of primary outcomes and primary safety outcomes.•Primary outcome: Stroke or systemic embolism

•Primary outcome was evaluated as total events and individual events in systemic embolism, ischemic stroke, and hemorrhagic stroke.

•Secondary outcomes: death from any cause, specifically:•Stroke or systemic embolism•Myocardial Infarction•Pulmonary embolism or DVT

•Primary safety outcomes: major bleeding classified by ISTH•Secondary safety outcomes: incidence of bleeding not classified as a major bleed.

Trial design: double-blind, double dummy with patients randomly assigned to apixaban or dose-adjusted warfarin. ◦ Patients were stratified into whether they have received

warfarin previously & clinical testing site. Patients previously on vit K antagonists were instructed

through a washout period and initiated with trial treatment when their INR fell below 2.0

◦ Apixaban or matching placebo administered in 5mg tab BID or decreased dose of 2.5mg BID if the patient was 80 years of age or older, a body weight less than 60kg, and a SCr 1.5mg/dL or more.

◦ Warfarin or matching placebo administered in 2mg tabs and titrated until goal INR of 2.0-3.0 was achieved. (each site used the same protocol for adjustment of warfarin)

In order to prove non-inferiority apixaban group needed at least 50% RR in primary outcomes (compared to 62% RR for warfarin)

Estimated that 448 patients with primary outcome would provide 90% power to ensure 99% confidence interval. ◦ Planned on recruiting 18,000

P-value for non-inferiority calculated one sided while superiority calculated using two sided calculations.

Primary and secondary efficacy analysis included the entire intended to treat population.

Non-inferiority (p<0.001) and superiority (p<0.01) established.

Hemorrhagic stroke had a 49% less incidence rate in apixaban group than warfarin.

There was a 7.7 absolute reduction in the incidence of bleeding the apixaban group versus the warfarin group.

A 27% relative reduction in incidence of major bleeding.

Overall, apixaban reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%.

Apixaban is more effective than warfarin for stroke prevention and is associated with a lower risk of bleeding.

Mentions Dabigatran◦ Shown to reduce rate of stroke with similar rates

of bleeding in comparison to warfarin. (RE-LY)◦ However, increase risk of GI bleed.

Mentions Rivaroxaban◦ Was only shown to be non-inferior to warfarin for

stork prevention (ROCKET AF) ◦ Rate of intracranial hemorrhage and fatal

bleeding were lower, however, no difference in rate for all other types of bleeding.

Strengths ◦ Large international population◦ Non-inferiority and superiority◦ Similar sample background in each arm◦ Assessment on several bleeding scales.

Limitations◦ Long term risk reduction (what does the curve

looks like after 2 to 3 years?)◦ Lists reasons for difference in other novel

anticoagulation trials: PK and PD properties of drug, patient populations, trial design

Pradaxa: direct thrombin inhibitor Rivaroxaban: selective inhibitor of Xa

◦ FDA approved drug but does not yet have the indication for AF.

Apixaban: selective inhibitor of Xa

Possible replacement of apixaban with warfarin especially in patients with high concerns for stroke or bleeding and patients non-compliant with restricted vitamin K diet.

Since Rivaroxaban and Apixaban have the same mechanism of action, studies may need to be done to determine non-inferiority/ superiority between the two.◦ Both have studies versus warfarin.