Stroke and Clot Prevention: New Guidelines and New Drugs?
Transcript of Stroke and Clot Prevention: New Guidelines and New Drugs?
Stroke and Clot Prevention:
New Guidelines and New Drugs?
Glenda Carr, PharmD
Clinical Assistant Professor of Pharmacy Practice
Disclosure
The planners and presenter of this presentation have disclosed no conflict
of interest, including no relevant financial relationships with any commercial
interests
Learning Objectives
Assess patient risk factors for developing stroke and VTE.
Cite and discuss recent anticoagulation guidelines for
stroke and VTE prevention.
Develop a therapeutic plan for first and recurrent stroke
and VTE prevention utilizing guideline recommendations
and incorporating individual patient factors.
Abbreviations AF- atrial fibrillation
PAF- paroxysmal atrial fibrillation
TE- thromboembolism
VTE- venous thromboembolism
PE- pulmonary embolism
DVT- deep vein thrombosis
NOAC- novel oral anticoagulant
VKA- vitamin K antagonist
CHF- congestive heart failure
LMWH- low molecular weight heparin
UFH- unfractionated heparin
COR- Class of recommendation
MVR- mechanical valve replacement
January CT, et al. Circulation 2014;130:e199–e267.
Brand/Generic
Thrombin Inhibitor
Dabigatran- Pradaxa®
Factor Xa Inhibitor
Rivaroxaban- Xarelto®
Apixaban- Eliquis®
Edoxaban- Savaysa®
Vitamin K Antagonist
Warfarin- Coumadin®
Considerations for Long Term
Anticoagulation
Risk of bleeding
HAS-BLED
ORBIT
Risk of stroke
A fib
Valve replacement
Risk of recurrent VTE
Distal vs. proximal location
Provoked vs. idiopathic
Other considerations
Patient preference
HAS-BLED
Hypertension (uncontrolled SBP >160 mmHg)
Abnormal renal and/or liver function
Previous Stroke
Bleeding history or predisposition (anemia)
Labile INR (only for VKA users)
Elderly (age ≥65)
Concomitant Drugs (antiplatelet, NSAIDs, alcohol excess)
Scoring
“Low risk” 0-1
“Moderate/intermediate risk” 2
“High risk” ≥3
ORBIT-AF Older than 74
Reduced Hb/presence of anemia/abnormal Hb/Hct
(<13 g/dl or Hct <40% in males and Hb <12 or Hct <36% in
females)
Bleeding history
Insufficient kidney function (GFR <60)
Treatment with antiplatelet
Scoring
“Low risk” 0-2
“Moderate/intermediate risk” 3
“High risk” ≥4
Calculate the bleeding risk using the HAS-
BLED for a 68 year old woman with a BP of
162/84, hx of CVA, and an AST level of 72.
A. 0
B. 1
C. 2
D. 3
E. 4
0 1 2 3 4
20% 20% 20%20%20%
Kearon C, et al. CHEST 2016;149:315-352.
Considerations for Long Term
Anticoagulation
Risk of bleeding
HAS-BLED
ORBIT
Risk of stroke
A fib
Valve replacement
Risk of recurrent VTE
Distal vs. proximal location
Provoked vs. idiopathic
Other considerations
Patient preference
Further Defining AF1
Summary of Recommendations1
Recommendations COR
Selection of therapy based on risk of TE I
CHA2DS2-VASc score to assess stroke risk I
Warfarin for mechanical heart valves I
Dabigatran should not be used with a
mechanical heart valve III
Treat atrial flutter like AF I
Utilize creatinine clearance to guide
therapy IIa-III
CHA2DS2-VASc
CHA2DS2 VASC Clinical characteristic Points
C Congestive heart failure 1
H Hypertension: Consistently >140/90
mmHg (or on medication)
1
A2 Age ≥ 75 2
D Diabetes Mellitus 1
S2 Stroke or TIA or Thromboembolism 2
V Vascular Disease (e.g. peripheral artery
disease, myocardial infarction, aortic
plaque
1
A Age 65-74 1
SC Sex Category (i.e. female gender) 1
Interpreting the Score1
CHA2DS2 VASC score Annual risk of stroke
0 0
1 1.3%
2 2.2%
3 3.2%
4 4.0%
5 6.7%
6 9.8%
7 9.6%
8 12.5%
9 12.2%
No
anticoagulation
required- IIa
May
consider
long term
treatment-IIb
Long term
treatment
should be
considered- I
If the earlier patient was a first degree
relative, would you consider long term
anticoagulation for atrial fibrillation?
Discuss your rationale with your neighbor
Treatment Selection for CHA2DS2-VASc
Score 0
Reasonable to omit therapy
Score 1
Aspirin may be considered
Score 2 or more
Warfarin (LOE A)
NOAC (LOE B)
Warfarin vs. NOAC: Meta-Analysis2
Randomized phase 3 trials
Safety and efficacy outcomes reported
Warfarin compared to NOAC
4 major trials included
RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy)
ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibition Compared With Vitamin K Antagonism for Prevention
of Stroke and Embolism Trail In Atrial Fibrillation)
ARISTOTLE (Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation)
ENGAGE AF-TIMI 48
Over 71,000 people included in analysis
Primary Outcomes2
Secondary Outcomes2
Stroke or Systemic Embolic Events2
Major Bleeding2
Nishimura RA, et al. Circulation. 2014; 129: e57-185.
MVR and Dabigatran6
RE-ALIGN trial (warfarin vs. dabigatran)
Dabigatran renal dosing
Warfarin dosed based on appropriate INR
Trial stopped early (252 enrolled)
Stroke 0% vs. 5% (n=9)
Valve thrombosis 0% vs. 3% (n=5)
Bleeding 12% vs. 27%
Major bleeding 2% (n=2) vs. 4% (n=7)
Considerations for Long Term
Anticoagulation
Risk of bleeding
HAS-BLED
ORBIT
Risk of stroke
A fib
Valve replacement
Risk of recurrent VTE
Distal vs. proximal location
Provoked vs. idiopathic
Other considerations
Patient preference
Chance of Recurrence
First unprovoked episode
10% at year one
30% at year five
5% per year after the first year
Prior treatment duration does not affect recurrence
Cancer 3x higher risk of recurrent VTE, 10x mortality rate
Harder to determine provoked recurrence rates
Definitions7
Guideline Recommendations3
Recommendations COR
Long term treatment is better than no treatment in proximal
DVT or PE
Ib
Long term NOAC treatment preferred to VKA in DVT of the
leg or PE (no cancer)
IIb
DVT of the leg or PE with cancer LMWH long term treatment
preferred over VKA/NOAC, regardless of bleeding risk
extended treatment recommended
IIb/IIc
Ib/IIb
Provoked DVT of leg or PE long term treatment over shorter,
longer time-limited period, or extended treatment
Ib
Unprovoked DVT of leg or PE long term treatment over
shorter, longer time-limited period, or extended treatment
Ib
Unprovoked first VTE with low-moderate bleeding risk
recommend extended treatment over long-term treatment
IIb
Unprovoked first VTE with high bleeding risk recommend
long-term treatment over extended treatment
Ib
Recurrent VTE3
Recommendation COR
Low bleeding risk extended anticoagulation therapy over
long term treatment
Ib
Moderate bleeding risk extended therapy over long term
treatment
IIb
High bleeding risk long term treatment over extended
treatment
IIb
While on treatment switch to LMWH at least temporarily IIc
Rivaroxaban or aspirin for extended
treatment of venous thromboembolism9
Inclusion 18 years of age or older
Symptomatic DVT or PE
Previous treatment for 6-
12 months
Exclusion Contraindication to
continued
anticoagulation
Required extended
anticoagulation
Creatinine clearance of
less than 30ml/min
Hepatic disease
N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.1056/NEJMoa1700518. Epub 2017 Mar 18
N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.1056/NEJMoa1700518. Epub 2017 Mar 18
Kearon C, et al. CHEST 2016;149:315-352.
Recommendations when using
warfarin1
During initiation, check INR at least weekly
Check INR monthly
Base bridging considerations on risk of clot with
bleeding risk
Consider NOAC if unable to maintain therapeutic INR
Why use a NOAC?2
Rapid onset and offset action
Lack of dietary interactions
Fewer drug interactions
No routine lab monitoring
Better outcomes?
Effectiveness8
Apixaban
(Eliquis)
Dabigatran
(Pradaxa)
Rivaroxaban
(Xarelto)
Edoxaban
(Savaysa)
A Fib • Per 1000
patients
treated per
year
o Prevents 3
more strokes
o Prevents 4
deaths
• Per 1000
patients treated
per year
o Prevents 5 more
strokes
o 2 more MIs
• Comparable for
stroke or
systemic
embolism
• Lower rate of
hemorrhagic
stroke
• Comparable
DVT/PE
(treatment/
prevention)
• Comparable • Comparable • Comparable • Comparable
Bleeding Events8
Apixaban (Eliquis) Dabigatran
(Pradaxa)
Rivaroxaban
(Xarelto)
Edoxaban
(Savasya)
A fib • Avoids 10 major
bleeds per 1000
patients treated
• Lower rate of
hemorrhagic
and ischemic
stroke
• Higher rate of
major GI Bleed
• Comparable
overall bleeding
• Higher rate of GI
bleeds
• Per 1000 patients per year 6
fewer bleeds
DVT/PE • Less bleeding • Comparable
major bleeding
• DVT-
comparable
major bleeding
or clinically
relevant non-
major bleeding
• PE- lower rate of
major bleeding
• Per 1000 patients per year 18
fewer bleeds
Apixaban (Eliquis®)8
Dosing
DVT and PE treatment: 10 mg BID x7 days, then 5 mg BID x6
months, then 2.5 mg BID
Non-valvular Atrial Fibrillation: 5 mg BID
2.5 mg BID if 2 of the following: Age ≥80 years, weight ≤60 kg,
or Sr Cr ≥1.5 mg/dL
Switching anticoagulation therapies
From warfarin: d/c warfarin when INR is <2 and initiate apixaban
To warfarin: d/c apixaban and begin a parenteral anticoagulant
with warfarin when the next dose of apixaban is due
Apixaban may interfere with initial INR readings
Drug Interactions
Avoid strong inducers of both CYP 3A4 and P-gp
Dabigatran (Pradaxa®)8
Dosing
DVT and PE treatment: 150 mg BID
Non-valvular Atrial Fibrillation: 150 mg BID
Switching anticoagulation therapies
From warfarin: d/c warfarin, start dabigatran when INR <2
To warfarin: start warfarin 1-3 days prior to d/c dabigatran
Drug Interactions
P-gp inhibitors increase levels
P-gp inducers decrease efficacy
Antacids reduce efficacy
Antidote: idarucizumab (Praxbind®)
Rivaroxaban (Xarelto®)8
Dosing
DVT and PE treatment: 15mg QD x3 weeks then, 20mg daily
Non-valvular Atrial Fibrillation: 20mg QD
Switching anticoagulation therapies
From warfarin: d/c warfarin and start rivaroxaban when INR <3
To warfarin: d/c rivaroxaban and begin a parenteral anticoagulant with warfarin when the next dose of rivaroxaban is due
Rivaroxaban may interfere with initial INR readings
Drug Interactions
Inducers of both CYP 3A4 and P-gp may decrease efficacy
Avoid strong inhibitors of both CYP 3A4 and P-gp
Edoxaban (Savasya®)8
Dosing
DVT and PE treatment: 60 mg QD, unless weight ≤60 kg then 30mg QD
Non-valvular Atrial Fibrillation: 60 mg QD
Switching anticoagulation therapies
From warfarin: d/c warfarin, then start edoxaban when INR ≤2.5
To warfarin: reduce edoxaban dose by 50% and start warfarin then continue until INR ≥2
Drug Interactions
Inducers of both CYP 3A4 and P-gp may decrease efficacy
Avoid strong inhibitors of both CYP 3A4 and P-gp
Renal Dosing1
If you had to use a long term anticoagulant,
which one would you choose?
A. Dabigatran (Pradaxa®)
B. Rivaroxaban (Xarelto®)
C. Apixaban (Eliquis®)
D. Edoxaban (Savaysa®)
E. Warfarin (Coumadin®)
Dabiga
tran (P
radaxa
®)
Rivaro
xaban
(Xare
lto®)
Apixaban
(Eliq
uis®)
Edoxa
ban (S
avays
a®)
Warfa
rin (C
oumad
in®)
20% 20% 20%20%20%
Why did you choose what you did?
Patient Preference and
Other Considerations8
Cost
Adherence
Medications
INR monitoring
Drug/food/alcohol interactions
GI bleed risk/history
Concern for anticoagulation reversal
Pregnancy
Dabigatran (Pradaxa®) $333.57
Rivaroxaban (Xarelto®) $333.27
Apixaban (Eliquis®) $359.92
Edoxaban (Savaysa®) $291.30
Warfarin (Coumadin®) <$5.00
Idaho Medicaid4
Selected References
1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130:e199–e267.
2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with
warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955-62.
3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE Disease: CHEST guideline and expert panel report. CHEST 2016;149:315-352.
4. http://healthandwelfare.idaho.gov/Medical/PrescriptionDrugs/PriorAuthorizationForms/tabid/206/Default.aspx (accessed 2/7/17)
5. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM III, Thomas JD. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129: e57-185.
6. Eikelboom, JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves.
N Engl J Med 2013; 369:1206-14.
7. Kearon C, Akl EA, Comerota AJ, et. al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141:e419-494.
8. PL Detail-Document, Comparison of Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. May 2016.
9. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017;376:1211-22.