2. Preventing Stroke in AFib
CASE l
- 65 yr. old female evaluated after noticing a faster heart rate.
-EKG reveals AFib rate controlled. Patient is asymptomatic.
- Hx – hypertension,PVD and hyperlipidemia
- No bleeding history.
CASE ll
- 85 yr. old female admitted to hospital for confusion. She is found
to have two subdural hematomas, one chronic and one acute.
- On chronic Coumadin Tx for permanent AFib.
- Hx of renal insufficiency(CrCl 28), hypertension, memory loss
and balance issues
3. PREVALENCE OF ATRIAL FIBRILLATION
AF is the most common cardiac arrhythmia
Accounts for 1/3 of arrhythmia related hospital admissions
Affects 0.4% to 1%(2.66 million) of the American Population
AF incidence is <0.1% per year in < 40 yr. old population
AF incidence increases 1.5% per year for men and 2.0% per
year for woman > 80 yrs of age.
STROKE IS THE MOST FEARED CONSEQUENCE OF AF
4. RISK OF STROKE IN ATRIAL FIBRLLATION
Stroke is the number-one cause of long term disability in AF
and the third-leading cause of death
Contribution of CV conditions to stroke diminish with age
except for AF
Stroke incidence due to AF in adults 50 to 59 years is 1.5% per
year, beyond 60 yrs. of age it increases almost exponentially
and in the 80 and older population increases to 23.5%
Stroke attributable to AF is higher in Asians particularly
woman
STROKE DUE TO AF IS MORE SEVERE AND MORE LIKELY
TO BE FATAL
5. EVIDENCE FOR ANTICOAGULATION THERAPY TO
PREVENT STROKE IN AF
Abundant clinical trials attest to the efficacy of anticoagulation to prevent stoke in
the setting of AF
A meta- analysis of 29 studies of warfarin use for primary and secondary stroke
prevention in AF reported a 64% risk reduction (relative)
NNT for preventing 1 stroke per year in 37 pts. for primary prevention and 12 pts.for
secondary prevention
Thromboprophylaxis, especially with warfarin, reduces the severity of stroke………
ASA not as effective
ASA and subtherapeutic warfarin(INR <2) reduced 30 day mortality 3 fold
With optimal anticoagulation (INR>2) therapy mortality was reduced 5 fold
6. RISK OF BLEEDING WITH WARFARIN THERAPY
Risk of major bleeding 2% to 7% per year
More common in pts. with supratherapeutic INR’s, age
>75yrs, chronic kidney disease, sustained systolic BP of >160
mmHg
Sensitivity to dietary changes, drug interactions and
variations in genetic pharmacokinetics can lead to a wide
range of INR’s and major complications
7. RISK OF STROKE IN AF
CHADS2 SCORE
Score
CHADS2
Score
NRAF adjusted stroke
Rate(%/yr)
CHF or EF <30%
1
0
1.9
Hypertension
1
1
2.8
Age > 75 years
1
2
4.0
Diabetes
1
3
5.9
Stroke/TIA
2
4
8.5
5
12.5
Risk Factor
(thromboembolic)
6
18.2
CHADS2 Score
0 -1 = Low risk
2-3 = Moderate risk
> = 3 = High risk
In a patient without a history of a major bleed a score of 2 or higher suggests the risk of
stroke without anticoagulation therapy is the same as the risk of bleeding with therapy
8. RISK OF STROKE IN AF
CHADS2-VASc
Risk Factor
Score
CHA2DS2
VASc Score
Adjustes Stroke
Rate (%/yr)
CHF
1
0
0.0
Hypertension
1
1
0.7
Age >=75 years
2
2
1.9
Diabetes
1
3
4.7
Stroke/TIA TE event
2
4
2.3
Vascular disease*
1
5
3.9
Aged 65 74 years
1
6
4.5
Sex – Female
1
7
10.1
14.2
100.0
*VASCULAR DISEASE IS DEFINED AS PRIOR MI, PVD OR AORTIC PLAQUE
9. ATRIA Risk Model for AFib
Risk Factor
Points Without
Prior Stroke
Age,
>85
75 to 84
65 to 74
<65
Female
Diabetes
CHF
Hypertension
Proteinuria
eGFR<45 or ESRD
6
5
3
0
1
1
1
1
1
1
Points With
Prior Stroke
9
7
7
8
1
1
1
1
1
1
0 to 5 points = low risk = event rate of<1%
6 points = moderate risk = event rate of 1% to <2%
7 to 15 points = high risk = event rate of >2%
13. DABIGATRAN – PRADAXA
RE-LY TRIAL
The Randomized Evaluation of Long Term Anticoagulation Therapy
Randomized 18,113 NVAF patients to receive dose adjusted warfarin(INR 2-3) or
Dabigatran (blinded doses of 110mg or 150mg B.I.D)
Follow up was for 2 years
Compared dabigatran and warfarin in its reduction of the incidence of the composite
endpoint, stroke(ischemic and hemorrhagic) and systemic embolism
Dabigatran in either dose was found to be non inferior to warfarin
The 150mg dose was found to be superior to warfarin in preventing thrombotic events
with the same risk of major hemorrhage
The 150mg dose caused an increased risk of MI in patients > = 75 years of age and an
increased risk of extracranial bleeding at both doses. The 110 mg dose showed less
major hemorrhage
14. RE-LY TRIAL
POST-HOC ANALYSIS
Patients who underwent cardioversion on two doses of dabigatran showed a lower rate of
stroke and bleeding risk
The results were comparable but insignificant when compared to patients on warfarin (the
parent study was underpowered to show a comparison in the setting of cardioversion )
Studied the efficacy and safety differences between dabigatran and warfarin with respect to
time in therapeutic range(TTR), INR of 2 to 3
-Divided into four quartiles or TTR(<57.1%, 57.1% - 65.5%, 65.5% - 72.6%,
>72.6%)
and
-With higher TTR quartiles warfarin showed lower rates of nonhemorrhagic
stroke
-With higher TTR quatiles dabigatran(150mg) did not show superiority to
warfarin in risk reduction for nonhemorrhagic stroke
-Dabigatran(110mg) showed a lower bleeding risk than warfarin, irrespective of TTR
-Dabigatran(150mg) showed a lower bleeding risk with a low TTR
15. DABIGATRAN – PRADAXA
PHARMACOKINETICS
Oral direct-acting thrombin antagonist
It is poorly absorbed and has a low bioavailability(6.8%)
Its half life is12 to 17 hours and is excreted mainly in the kidneys(80%)
Dabigatran requires a low stomach ph for absorption and contains tartaric acid
Patients on protein pump inhibitors can experience decreased absorption
Dabigatran is a P-glycoprotein substrate and taken with drugs that are P-glycoprotein
inhibitors absorption in the gut is increased, increasing plasma concentration (i.e.,
amiodarone, cyclosporine, verapamil, ritonavir, ketoconazole)
P-glycoprotein inducers might reduce dabigatran plasma concentration(i.e., St John’s Wort,
rafampicin or carbamazepine)
No monitoring needed
NO CURRENT ANTIDOTE FOR PRADAXA
Should not be used in patients with prosthetic values, severe renal failure, advanced liver
disease and hemodynamically significant valve disease
16. DABIGATRAN - PRADAXA
Rx INFORMATION #1
•
•
•
•
Dabigatran comes in 75mg, 110mg(not available in USA) and 150mg
Dosing depends on renal function(80% excreted in the kidneys). Assess CrCl
- CrCl > 30mL/min use 150mg B.I.D.
- CrCl 15 - 30ml/min use 75mg B.I.D.
- CrCl <15 mL/min or on dialysis no dosing recommendations
Switching from warfarin to Pradaxa
-Allow the INR to drop to < 2 then start Pradaxa as per CrCl
Switching from Pradaxa to warfarin
- CrCl >=50 start warfarin 3 days before stopping Pradaxa
- CrCl 30 to 50 mL/min start warfarin 2 days before stopping Pradaxa
- CrCl 15 to 30 mL/min start warfarin 1 day before stopping Pradaxa
- CrCl <15 mL/min no recommendations
17. DABIGATRAN - PRADAXA
Rx INFORMATION # 2
•
•
Surgery and Interventions
- CrCl >=50 mL/min stop Pradaxa 1 to 2 days prior to surgery
- CrCl <50 mL/min stop Pradaxa 3 to 4 days prior to surgery
-Parenteral anticoagulants
- Currently on: - SQ - Start Pradaxa 0 to 2 hrs. before the next dose
Heparin - IV - Start Pradaxa at the time of discontinuing --- Taking
-CrCl >= 30mL/min wait 12 hrs. before starting
Pradaxa
- CrCl < 30mL/min wait 24 hrs.before starting
18. RIVAROXABAN - XARELTO
ROCKET AF TRIAL
The Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonist for
Prevention of Stroke and Embolism Trial in Arial fibrillation
•14,264 patients with NVAF
•Double blinded randomized trial with one group receiving 20mg/15mg of rivaroxaban and the
other group receiving dose adjusted warfarin(INR 2 to 3)
•Follow up was for a median of 590 days with primary endpoints of stroke or embolism
•Rivaroxaban proved to be noninferior to warfarin with no difference in major bleeding
•Rivaroxaban was associated with a lower frequency of intracranial and fatal bleeding
19. •
•
•
•
•
•
•
•
RIVAROXABAN - XARELTO
PHARMACOKINETICS
Factor Xa inhibitor
High bioavailability dependent on dose(80% to 100% with 10mg, 66% with 20mg)
Half life is 5 to 9 hrs.and is metabolized by both the liver and kidneys
Potential for drug interaction is high
-Rivaroxaban is metabolized through the CP450(CYP3A4) and is also a
P-glycoprotein substrate…..inhibition or induction can lead to increased or
decreased plasma concentrations
Dosing depends on renal function(not recommended in moderate or severe
hepatic dysfunction)
No monitoring needed
NO ANITODOTE AVAILABLE
Several under investigation……PCC reversed rivaroxaban but not dabigatran
20. •
•
•
•
•
•
•
•
RIVAROXABAN - XARELTO
Rx INFORMATION
Available in 10mg, 15mg and 20mg
Dosing depends on renal function
- CrCl >50 mL/min 20mg qd with the evening meal
- CrCl 15 to 50mL/min 15mg qd with the evening meal
- CrCl< 15 mL/min avoid use
Switching from warfarin
-Stop wafrain and start Xarelto when the INR is < 3
Switching to warfarin
- No clinical trial data is available
- DC Xarelto and begin both a parenteral anticoagulant and wafarin at the time when the next dose of
Xarelto is due
Switching from anticoagulants other than warfarin
- SQ - Start Xeralto 0-2 hrs.before the next evening dose and DC the anticoagulant
- IV - DC IV infusion and start Xarelto immediately
- Surgery and interventions
- Stop Xarelto 24 hrs. before surgery
- Restart 6 to 10 hrs. after hemostasis obtained
21. APIXABAN-ELIQUIS
ARISTOTLE TRIAL
Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF
18,201 patients with NVAF and one additional risk factor
Double blinded randomized trial comparing Apixaban(5mg B.I.D.) with dose adjusted
warfarin(INR 2-3)
Followed for a median of 1.8 years
Apixaban proved to be superior to wafarin in preventing stroke or systemic emboli
Reduced risk of intracranial bleeding, fatal bleeding and mortality rate
AVERROES compared ASA to apixaban in patients not candidates for Vitamin K antagonists
-Apixaban as compared to ASA reduced the risk of stroke and emboli by >50%
-THE DIFFERENCE IN MAJOR BLEEDING WAS NOT SIGNIFICANT
22. APIXABAN
PHARMOKINETICS
Factor Xa inhibitor
Bioavailability of 50%
Half life of 9 to 14 hrs.
Metabolized 1/3 in the kidneys and 2/3 in the liver via the CYP3A4
Inhibitors or inducers of both CYP3A4 and P-glycoprotein may affect its absorption and plasma
concentrations
Dosage - 2.5mg or 5mg B.I.D.
For the 2.5mg dosage two of the following must be present:
1- >80yrs. of age, 2-<60 kg. 3-serum creatinine > 1.5mg/dl
DC prior to surgery-24hrs for low risk of bleeding/48hrs for high risk
Switching from warfarin-begin apixaban when the INR is < 2
Switching to warfarin-begin when the next dose is due.
High risk-heparin bridge
27. Preventing Stroke in AFib
CASE l
- 65 yr. old female evaluated after noticing a faster heart rate.
-EKG reveals AFib rate controlled. Patient is asymptomatic.
- Hx – hypertension,PVD and hyperlipidemia
- No bleeding history.
CASE ll
- 85 yr. old female admitted to hospital for confusion. She is found
to have two subdural hematomas, one chronic and one acute.
- On chronic Coumadin Tx for permanent AFib.
- Hx of renal insufficiency(CrCl 28), hypertension, memory loss
and balance issues
28. CONCLUSIONS
•
•
•
•
•
•
The decision to use thromboprophylaxis for AF requires the judicious
and objective evaluation of bleeding and stroke risks
Deciding to initiate and maintain anticoagulation therapy is often
difficult for physicians because of important safety concerns that are
not manifested in the current and rather imprecise scoring mechanisms
The Novel Anticoagulants compare favorably with warfarin in terms of
efficacy and bleeding risks. Despite claims that monitoring is not
required, monitoring provides a measure of safety, efficacy and compliance
The development of antidotes to safer and more easily controlled
anticoagulants, might then enable the accurate, precise and safe
application of thromboprophylaxis in patients with AF
Warfarin remains effective for stroke prophylaxis
In trials that compare warfarin to the “new kids on the block,” patients
with stable and good control may not benefit by changing to new drugs
Arthur J Muller D.O.