Advancements
In Anticoagulation
June 14, 2013
Dosha Cummins, PharmD, BCPS
UAMS Northeast
Associate Professor
Dept. of Pharmacy Practice
Dept. of Family and Preventive Medicine
Direct Thrombin Inhibitors
IV
• Bivalirudin (Angiomax®)
• PCTA
• Desirudin (Iprivask®)
• DVT/hip
• Argatroban (Argatroban™)
• HIT
Oral
• Dabigatran (Pradaxa®)
• Prevention of stroke in a fib- 10/10
Dabigatran (Pradaxa®)
• Prodrug
• Dabigatran etexilate → hydrolyzed by esterase to
dabigatran
• Tartaric acid in product improves absorption
• 80% renally eliminated
• 68% dialyzed at 4 hours
• P-glycoprotein (P-gp) pumps
• (rifampin, ketoconazole; adjustment not required for
verapamil, amiodarone, quinidine, clarithromycin)
• Discard 4 months after bottle opened
Dabigatran (Pradaxa®)
• To prevent stroke in non-valvular atrial fibrillation
• RE-LY Trial
• N=18,113
• Mean CHAD2 score 2.1
• Mean age 72 years
• Excluded: stroke within 14 days prior or severe stroke
within 6 months
• Dabigatran 110mg bid vs dabigatran 150mg bid vs
dose-adjusted warfarin
Dabigatran (Pradaxa®)
• Results
• Primary endpoint stroke/systemic embolism
• 1.11% dabigatran 150mg bid vs 1.71% warfarin
• NNT for 1 year to prevent 1 stroke/systemic
embolism = 167
• About 6 events prevented per 1000 patients treated
for 1 year
• Adverse Effects
• Intracranial bleed: NNT=227
• GI bleed: NNT= 204
Dabigatran (Pradaxa®)
• Results
• Primary endpoint stroke/systemic embolism
• 1.11% dabigatran 150mg bid vs 1.71% warfarin
• NNT for 1 year to prevent 1 stroke/systemic
embolism = 167
• About 6 events prevented per 1000 patients treated
for 1 year
• Adverse Effects
• Intracranial bleed: NNT=227
• GI bleed: NNT= 204
• “Suggested” over warfarin (Grade 2B) – CHEST 2012
Dabigatran (Pradaxa®)
• Dosing for prevention of stroke in atrial fibrillation
• CrCl > 30mL/min - 150mg bid (with or without food)
• CrCl 30-50mL/min on ketoconazole or dronedarone,
consider adjusting to 75mg bid
• CrCl 15-30mL/min – 75mg bid; avoid P-gp inhibitors
• CrCl <15mL/min or dialysis – avoid
• Avoid with P-gp inducers (rifampin)
Direct Xa Inhibitors
IV
Oral
• Fondaparinux (Arixtra®) • Rivaroxaban (Xarelto®)
• VTE
• Ortho VTE prophylaxis-7/11
• Prevention of stroke in a fib-11/11
• PE/DVT treatment-11/12
• Apixaban (Eliquis®)
• Prevention of stroke in a fib-12/12
Rivaroxaban (Xarelto®)
• Absorption – dose dependent
• 10mg (80-100%)
• 20mg (66%) – increased by 76% with food
• Drug released in stomach (AUC decreases by 29% via
feeding tube into proximal small intestine)
• Metabolized in liver by CYP3A4/5 and CYP2J2; P-gp
substrate
• Avoid meds that can inhibit/induce both systems
(erythromycin, clarithromycin, ketoconazole,
fluconazole; rifampin, phenytoin, CBZ, St. John’s
Wort)
• Not dialyzable
Rivaroxaban (Xarelto®)
• To prophylaxis for DVT/PE in knee and hip replacement
Population
Comparer
Results
NNT
RECORD 1
Hip
arthroplasty
40mg enoxaparin
1.1% vs 3.7%
38
(at 35 days)
RECORD 3
Knee
arthroplasty
40mg enoxaparin
9.6% vs 18.9%
11
(at 2 weeks)
RECORD 4
Knee
arthroplasty
30mg bid enoxaparin
6.9% vs 10.1%
32
(at 17 days)
Rivaroxaban (Xarelto®)
• To reduce the risk of stroke and embolism in atrial
fibrillation
• ROCKET-AF Trial
• N= 14,264
• Mean CHAD2 score 3.5
• Mean age 73 years
• Excluded: stroke within 14 days or TIA within 3 days,
GI bleed within 6 months
• Rivaroxaban 20mg* daily vs dose-adjusted warfarin
* 15mg daily if CrCl 30-49mL/min
Rivaroxaban (Xarelto®)
• Results
• Primary endpoint stroke/systemic embolism
• 2.1% rivaroxaban vs 2.4% warfarin
• NNT for 1 year to prevent 1 stroke/systemic
embolism = 330
• About 3 events prevented per 1000 patients
treated for 1 year
• Adverse Effects
• Intracranial bleed: NNT= 500
• GI bleed: NNT= 100
Rivaroxaban (Xarelto®)
• To treat DVT, PE and reduce the risk of recurrence
• EINSTEIN-PE Trial
• N=4832 with confirmed, symptomatic PE
• 15mg rivoroxaban bid x 3 weeks, then 30mg daily vs
enoxaparin + vitamin K antagonist
• Randomized to 3, 6 or 12 months
• Primary endpoint: symptomatic, recurrent VTE
• 2.1% rivaroxaban vs 1.1% standard therapy
• NNT= 333 (mean study duration ∼ 263 days)
• NNT for major bleeding = 91
Rivaroxaban (Xarelto®)
• Acute coronary syndrome – ATLAS ACS
• June 2012
• FDA rejected 6:4
• Reduced risk of stroke by 15%
• 2.5 or 5 mg bid vs placebo
• N=15,526
• FDA cited incomplete outcome data for 12% of study
participants
Rivaroxaban (Xarelto®)
• Ortho VTE prevention:
• Hip: 10mg/d x 35 days (with/without food)
• Knee: 10mg/d x 12 days (with/without food)
• CrCl < 30mL/min - avoid
• Stroke prevention in atrial fibrillation:
• 20mg/d daily with evening meal
• CrCl 15-50mL/min - 15mg/d with evening meal
• CrCl <15mL/min – avoid
• PE/DVT treatment:
• 15mg bid x 3 weeks, then 20mg daily
• CrCl15-49mL/min – 15mg bid x 3 weeks, then 20mg daily
• CrCl <15mL/min – avoid
Apixaban (Eliquis®)
• Absorbed in small intestine and colon
• Metabolized by CYP3A4 and a P-gp substrate
• Reduce dose to 2.5mg bid if on ketoconazole,
itraconazole, clarithromycin (avoid if already on
apixaban)
• Avoid dual inducers: rifampin, CBZ, phenytoin,
St. John’s Wort
• Not dialyzable
Apixaban (Eliquis®)
• To reduce the risk of stroke and embolism in atrial fibrillation
• ARISTOTLE Trial
• N= 18,201
• Mean CHAD2 score 2.1
• Mean age 70 years
• Included:
• More than 1: ≥ 75 years, prior stroke/TIA/systemic
embolus; symptomatic CHF, DM, HTN, female
• Excluded: CVA within 7 days, ASA dose ≥ 165mg/day
• Apixaban 5 mg bid* vs dose-adjusted warfarin
*2.5mg bid if ≥ 2 of the following: ≥80 years, ≤60 kg, or Scr ≥ 1.5mg/dL
Apixaban (Eliquis®)
• Results
• Primary endpoint stroke/systemic embolism
• 1.27% apixaban vs 1.6% warfarin
• NNT for 1 year to prevent 1 stroke/systemic
embolism = 303
• About 3 events prevented per 1000 patients
treated for 1 year
• Adverse Effects
• Intracranial bleed: NNT= 212
• GI bleed: NNT= NS
Apixaban (Eliquis®)
• Stroke prevention in atrial fibrillation:
• 5mg bid
• 2.5mg bid ≥ 2 of the following:
• ≤60kg, ≥80yrs, Scr ≥1.5mg/dL
Prosthetic Heart Valve Patients
• Pradaxa®
• Contraindicated for patients with mechanical heart
valve - December 2012
• RE-ALIGN Trial
• Dabigatran patients more likely to experience
stroke or major thromboembolic event vs warfarin
• Dabigatran patients had more bleeding after valve
surgery
• Xarelto® & Eliquis®- not recommended
Atrial fibrillation
Per year
NNT to
prevent
an event
Additional
events
prevented per
1000 patients
NNT for Major
Bleed
TTR
(Warfarin
Patients)
Dabigatran
(CHAD2- 2.1)
167
∼6
400
64%
Rivaroxaban
(CHAD2 - 3.5)
330
∼3
500
55%
Apixaban
(CHAD2 -2.1)
303
∼3
104
62%
TTR – Time in Therapeutic Range
Risk of Bleeding with Antithrombotic Treatment
4.5
4.03
4
3.57
RR (relative risk)
3.5
3
2.5
1.75
2
1.45
1.5
1
1.91
0.96
1.0
0.5
0
ASA
warfarin Plavix® warfarin Plavix® warfarin warfarin
+
+
+
+
ASA
ASA
Plavix® Plavix®
+
Arch Intern Med 2010;170(16):1433-1441
ASA
Dabigatran
Rivaroxaban
Apixaban
Absorption and
crushing
Do not break/chew
Can crush and
suspend in 50ml of
water to administer
via NG or gastric
tube; follow with
feeds
N/A
Affect of food on
bioavailability
None
20mg dose – food
increases
None
Product
Monitoring New Agents
• INR – specifically calibrated to monitor vitamin K
antagonists
• New agents affect, but no correlation with efficacy or
safety
• May affect first 2 days when transitioning to warfarin
• Direct thrombin inhibitors (dabigatran)
• Diluted thrombin time (TT) evolving
• Factor Xa inhibitors (rivaroxaban & apixaban)
• PT affected more than PTT
• Linear response, but reagent specific
Reversing New Agents
• Dabigatran (Pradaxa®)
• 60% dialyzed
• Distributes to tissue early, then serum rebound
• Rivaroxaban (Xarelto®) & Apixaban (Eliquis®)
• Not dialyzed
• Prothrombin Complex Concentrate (PCC)
• Factor VII
General Reminder for New Agents
• Avoid “indication creep”
• Avoid in patients with a prosthetic heart valve
• Be vigilant in dosing adjustments
• Changes in renal function
• Changes in indications (post-ortho patient diagnosed
with atrial fibrillation)
• Compliance is extremely important because of short
duration of effects
SPECIFIC POPULATIONS
Atrial fibrillation and Stents
• Chest. 2012; 141(suppl 2): e531S-e575S
• CHAD2 score ≥ 2 (Grade 2C)
• Triple therapy duration (warfarin + DAPT)
• Bare-metal stent – 1 month
• Drug-eluting stent – 3 months
• After triple therapy, continue warfarin and a single
anti-platelet agent until 12 months after stent
placement
• After 12 months, warfarin alone
• CHAD2 score 0-1 (Grade 2C)
• DAPT for 12 months
Atrial fibrillation and ACS
• CHADS2 score ≥ 1 with ACS not receiving stents
• Warfarin plus single anti-platelet therapy for the first
12 months rather than DAPT or triple therapy x12
months (Grade 2C)
• CHADS2 score of 0 or 1
• DAPT recommended over warfarin plus single
antiplatelet therapy or triple therapy x 12 months
(Grade 2C).
• After the first 12 months, antithrombotic therapy is
suggested as for patients with AF and stable coronary
artery disease (eg, warfarin only) (Grade 2C)
Atrial fibrillation and Stable CAD
• If on warfarin and no ACS within past year, warfarin only
recommended over warfarin plus aspirin. (Grade 2C)
PRIMARY PREVENTION WITH ASA
USPSTF¶
Men
Women
MI
<49 years: ASA not recommended
Age 45-79 years: ASA benefit
outweighs GI bleed risk
ASA not recommended
ASA not recommended
<55 years: ASA not recommended
55-79 years: ASA if benefit
outweighs GI bleed risk
Stroke
ADA#
Diabetics >50 years*
Diabetics >60 years*
*Consider ASA (81-162 mg/day) if ≥ 1 risk factor (family history or CVD, HTN, smoking,
dyslipidemia or albuminuria)
¶AHRQ
Publication No. 09-05129-EF-2, March 2009;
#
Diabetes Care. 2013; (36):S
Outpatient PE Treatment
• CHEST 2012;141;e419S-e494S
• 5.5 In patients with low-risk PE whose home
circumstances are adequate, we suggest early discharge
over standard discharge (eg, after 5 days of treatment)
Grade 2B
Potential Outpatient Candidates
Based on acute symptomatic PE, PESI – PE Severity Index
1. Clinically stable with good cardiopulmonary reserve
• PESI score <85 or simplified PESI of 0 if none of:
• SBP < 100
• Recent bleeding
• Severe chest pain
• Platelets <70,000/mm3 (on anticoagulant therapy)
• Severe hepatic or renal disease
2. Good social support with ready access to medical care
3. Expected to be compliant with follow-up
LMWH Dosing
• 5.4.2. In patients with acute PE treated with LMWH,
we suggest once- over twice-daily administration
(Grade 2C) .
• Remarks: This recommendation only applies when the
approved once-daily regimen uses the same daily dose
as the twice-daily regimen (ie, the once-daily injection
contains double the dose of each twice-daily injection). It
also places value on avoiding an extra injection per day.
Avoid ‘Bridging a Bridge”
… using newer anticoagulants
instead of heparin while waiting
for a therapeutic INR
Clopidogrel: Treatment Failure vs Resistance
• Treatment failure (clinical observation)
• Non-compliance
• Individual variation in ADP-mediated platelet response
• Resistance
• In-complete blockade of P2Y12 receptor
• Proton pump inhibitors
• Clopidogrel label
• Includes omeprazole & esomeprazole as DI’s
• Pantoprozole will be moved to preferred status by AR
Medicaid July 9th, esomeprazole moved to nonpreferred
Genotype Variability
• P2Y12 receptor variability
• Drug transport (MDR1)
• CYP2C19 has >25 known variant alleles
• Most common dysfunction
• ∼15% of Caucasians and Africans
• 29-35% Asians
Clin Pharmcol Ther 2011;90(2): 329-332
• Testing not universally recommended by ACC
• ACCF/ACG/AHA 2010 Expert Consensus Document on
the Concomitant Use of PPI’s and Thienopyridones.
JACC 2010; 56(24): 2051-2066
VerifyNow® Results
% Inhibition
Threshold
PRU
Threshold
10
259
20
237
30
214
40
187
50
159
60
131
ADP 2Y12 assay
• Light transmission platelet aggregometry endorsed by
platelet specialists as standard of care
• Available assays correlate poorly with each other and
only modestly predict clinical outcome (sensitivity 5563%, specificity 59-64%)
• Other medications can interfere with assays
• Lack of universally accepted cut-off value for resistance
• “Bedside monitoring” and dose adjustment hasn’t been
shown to be beneficial (NEJM 2012;367:2100-2109)
References
RE-LY
Connolly, SJ, Ezekowitz MD, Yusuf S, et al. NEJM 2009;361:1139-1151.
RECORD 1 Eriksson BI, Borris LC, Friedman RJ, et al. NEJM 2008;358:2765-75.
RECORD 3 Lassen MR, Angeo W, Borris LC, et al. NEJM 2008;358: 2776-86.
RECORD 4 Turpie AG, Lassen MR, Davidson BL, et al. Lancet 2009;373:1673-80.
ROCKET AF Patel MR, Mahaffey KW, Garg J, et al. NEJM 2011; 365:883-891.
EINSTEIN-PE Einstein investigators. NEJM 2012;366:1287-97.
ARISTOTLE Granger CB, Alexander H, McMurray JJV, et al. NEJM 2011.
365:981- 992
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;
141(suppl 2):
http://www.mdcalc.com/simplified-pesi-pulmonary-embolism-severity-index/
Collet JP, Cuisset T, Range G, et al. NEJM 2012;367:2100-2109