Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18, 2012 [email protected]
This presentation will discuss unlabeled and investigational use of products
The author has no disclosures
2.5 million Americans live with atrial fibrillation (afib)
Afib-associated morbidity and mortality
Annual incidence of stroke in patients with afib: 5%
Risk of stroke increases with age
Reprinted from AF Stat™: A Call to Action for Atrial Fibrillation; Accessed via www.AFStat.com
2010 AHA/ASA guidelines for the primary prevention of stroke
2010 AHA/ASA guidelines for prevention of stroke in patients with ischemic stroke or TIA 2012 ACCP evidence-based clinical practice guidelines: antithrombotic therapy for atrial fibrillation and prevention of thrombosis, 9
thEd.
2012 AHA/ASA advisory on oral
antithrombotic agents for the prevention of
stroke in nonvalvular atrial fibrillation
Which patients with afib need stroke prevention therapy?
Risk stratification: CHADS2 Score ≥ 2
Risk Factor Points
Congestive heart failure 1
Hypertension 1
Age ≥ 75 years 1
Diabetes 1
Stroke or TIA 2
CHADS2 score
Risk group
Recommendation (Level of evidence)
Annual absolute risk
ASA VKA
0 Low Nothing or ASA only (2B) 0.6% 0.3%
1 Moderate Anticoagulation (1B) 1.7% 0.8%
2 High Anticoagulation (1A) 3.6% 1.7%
3-6 High Anticoagulation (1A) 7.6% 3.6%
ASA: Aspirin; VKA: Vitamin K antagonist
Antithrombotic therapy and prevention of thrombosis, 9thEd: ACCP Guidelines
Safety Efficacy
FDA approved October 2010
150 mg PO BID for CrCL > 30 mL/min
75 mg PO BID for CrCL 15-30 mL/min (not studied) Unique mechanism of action: direct thrombin inhibitor (argatroban, bivalirudin)
150 mg dose demonstrated superior efficacy and similar bleeding rates vs. warfarin (RELY)
Mean CHADS2 score: 2.1
Connolly SJ. N Engl J Med 2009;361(9):1139-1151.
Furie KL. Stroke 1012;43:00-00.
Event Warfarin (INR 2-3)
Dabigatran 150
mg BID P Value
Stroke
Hemorrhagic Ischemic
1.69%
0.38%
1.20%
1.11%
0.10%
0.92%
< 0.001
< 0.001 0.03 Major bleeding
Intracranial Life threatening Gastrointestinal
3.36%
0.74%
1.80%
1.02%
3.11%
0.30%
1.45%
1.51%
0.31
< 0.001 0.04
< 0.001
Dyspepsia 5.8% 11.3% < 0.001
Myocardial infarction (MI) 0.53% 0.74% 0.048
All results reported as % per year Connolly SJ. N Engl J Med 2009;361(9):1139-1151.
RELY substudy: platelet function test No difference in platelet activation between warfarin and dabigatran groups
Meta-analysis supports increase risk of MI Risk of MI/ACS: 1.19% dabigatran vs. 0.79%
comparator (P = 0.03)
Uchino K. Arch Intern Med 2012;172(5):397-402.Ferreira J. Thrombosis 2012 Uchino K. Arch Intern Med 2012
ACCP 9
thEd. (January 2012)
For those with atrial fibrillation and risk score favoring anticoagulation, dabigatran
recommended rather than VKA therapy (2B) with the exception of patients with the following:
▪ Mitral stenosis
▪ Active coronary artery disease (CAD) or history of CAD
You JJ. Chest 2012;141(2)Suppl:e531s-e575s.
AHA/ASA Advisory (August 2012)
“Dabigatran Is useful as an alterative to warfarin…
in patients who do not have a prosthetic heart valve or hemodynamically significant valve disease,
severe renal failure, or advanced liver disease (1B).”
Furie KL. Stroke 2012;43:00-00.
•
Lack of monitoring does not always prove beneficial
•
Renal function must be monitored closely
•
Lack of reversal agent
•
New Zealand experience identifies 4 items likely contributing to bleeding complications:
– Prescriber error (renal impairment, bridging off warfarin) – Acute changes in renal function
– Patient age and weight, especially > 80 years and < 60 kg – Complications secondary to prolonged half-life and lack of
reversal
Harper P. N Engl J Med 2012;366;9:864-866.
FDA approved November 2011
20 mg PO daily with meal for CrCL > 50 mL/min 15 mg PO daily with meal for CrCL 15-50 mL/min Mechanism of action: Inhibitor of factor Xa Similar efficacy and similar bleeding rates vs. warfarin (ROCKET AF)
Mean CHADS2 score: 3.5
Patel MR. N Engl J Med 2011;365;10: 883-891.
Event Warfarin
(n=7125)
Rivaroxaban
(n=7111) P Value
Stroke
Hemorrhagic
2.2%
1.2%
1.7%
0.8%
< 0.001*
0.02
Major bleeding 5.4% 5.6% 0.31
Myocardial
infarction 1.1% 0.9% 0.12
All results reported as % per year
*Results reported for per protocol analysis (n=7004 for warfarin and n=6958 for Rivaroxaban) and as non-inferiority
Patel MR. N Engl J Med 2011;365;10: 883-891.
ACCP Antithrombotic guidelines: no recommendation to date
AHA/ASA
In patients with CrCL > 50 mL/min and afib at high risk of stroke (CHADS2 ≥ 2), rivaroxaban is a
reasonable alternative to warfarin (IIa)
▪ The safety and efficacy of the renally adjusted dose has not been clearly established (IIb)
•
Lack of monitoring does not always prove beneficial
•
Safety and efficacy with renal and hepatic dysfunction not clearly established
•
Lack of reversal agent
•
Lack of post-marketing surveillance
Harper P. N Engl J Med 2012;366;9:864-866.
•
Not yet FDA approved
–
Studied as 5 mg PO BID
–
2.5 mg PO BID suggested in patients with at least two of the following:
–Age ≥ 80 years, weight ≤ 60 kg, creatinine ≥ 1.5 mg/dL
•
Mechanism of action: Inhibitor of factor Xa
•
Superior efficacy and safety vs. warfarin (ARISTOTLE)
•
Mean CHADS2 score: 2.1
Granger CB. N Engl J Med 2011;365:981-992.
Event Warfarin
(n=9081)
Apixaban
(n=9120) P Value Stroke
Hemorrhagic Ischemic
1.60%
0.47%
1.05%
1.27%
0.24%
0.97%
0.01
< 0.001 0.42 Major bleeding
Intracranial Gastrointestinal
3.09%
0.80%
0.86%
2.13%
0.33%
0.76%
< 0.001
< 0.001 0.37 Myocardial
infarction 0.61% 0.53% 0.37
All-cause mortality 3.94% 3.52% 0.047
All results reported as % per year
Granger CB. N Engl J Med 2011;365:981-992.
ACCP Antithrombotic guidelines: no recommendation to date
AHA/ASA
If CHADS2 score ≥ 1 and VKA unsuitable, apixaban is reasonable alternative to ASA therapy (I)
If CHADS2 score ≥ 2, apixaban is reasonable alternative to VKA therapy (I)
▪ If either of above is true and patient has > 1 risk factor for decreased drug clearance (age, weight, creatinine), consider lower dose alternative (IIb)
▪ Avoid apixaban if CrCL < 25 mL/min (Class III)
Never bridge No monitoring
Consider all factors that may lead to drug accumulation
Route of elimination: renal +/- hepatic Drug interactions due to CYP3A4 or P- glycoprotein
Advanced age or low body weight
Warfarin Class I
• INR goal 2-3
Dabigatran Class I
• Dose adjust based on CrCL and drug interactions
• Level of evidence lower for renally adjusted dose, avoid if CrCL < 15 mL/min
Apixaban Class I
• Dose adjust based on age, weight, creatinine*
• Level of evidence lower for renally adjusted dose, avoid if CrCL < 25 mL/min
Rivaroxaban Class IIa
• Dose adjust based on CrCL
• Avoid if CrCL < 15 mL/min or moderate-severe hepatic dysfunction
*Drug/dosing not currently FDA approved
Contraindicated with therapeutic warfarin 2007 Stroke Guidelines recommend INR ≤ 1.7 Dabigatran: not recommended
Normal aPTT and thrombin time suggest complete elimination of dabigatran
Rivaroxaban: not recommended
Normal PT may suggest complete elimination of rivaroxaban
Apixaban: not recommended
Adams HP. Stroke 2007;38:1655-1711
MINIMIZE ABSORPTION
Activated charcoal if ingestion occurred within 2 hours MINIMIZE ABSORPTION
Activated charcoal if ingestion occurred within 2 hours
MAXIMIZE RENAL ELIMINATION Assure adequate hydration & diuresis
Hemodialysis: 68% of drug is removed in a 4-hour dialysis session MAXIMIZE RENAL ELIMINATION
Assure adequate hydration & diuresis
Hemodialysis: 68% of drug is removed in a 4-hour dialysis session
BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT FFP will not reverse the coagulopathy of dabigatran BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT
FFP will not reverse the coagulopathy of dabigatran
OTHER AGENTS
Non-specific reversal agents? Activated PCC, rFVIIa Monoclonal antibody
OTHER AGENTS
Non-specific reversal agents? Activated PCC, rFVIIa Monoclonal antibody
PCC: Prothrombin complex concentrate, rFVIIa: recombinant activated factor VII
MINIMIZE ABSORPTION
Activated charcoal if ingestion occurred within 2 hours MINIMIZE ABSORPTION
Activated charcoal if ingestion occurred within 2 hours
BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT FFP will not reverse the coagulopathy of dabigatran BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT
FFP will not reverse the coagulopathy of dabigatran
OTHER AGENTS Non-specific reversal agents?
Activated PCC, PCC, rFVIIa OTHER AGENTS Non-specific reversal agents?
Activated PCC, PCC, rFVIIa
PCC: Prothrombin complex concentrate, rFVIIa: recombinant activated factor VII
Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18, 2012 [email protected]