Dosha Cummins, PharmD - Arkansas Academy of Family Physicians

Report
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

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