Advancements In Anticoagulation June 14, 2013 Dosha Cummins, PharmD, BCPS UAMS Northeast Associate Professor Dept. of Pharmacy Practice Dept. of Family

Advancements In Anticoagulation

June 14, 2013

Dosha Cummins, PharmD, BCPSUAMS Northeast

Associate ProfessorDept. 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


• 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


• 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



• 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


• 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• Fondaparinux (Arixtra®)

• VTE

Oral• Rivaroxaban (Xarelto®)

• 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


• To prophylaxis for DVT/PE in knee and hip replacement

Population Comparer Results NNT

RECORD 1Hip arthroplasty

40mg enoxaparin 1.1% vs 3.7%38

(at 35 days)

RECORD 3Knee arthroplasty

40mg enoxaparin 9.6% vs 18.9% 11

(at 2 weeks)

RECORD 4Knee arthroplasty

30mg bid enoxaparin 6.9% vs 10.1%32

(at 17 days)


• 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



• 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


• 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


• 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


• 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


• 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



• 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


• 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 yearNNT 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

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5Risk of Bleeding with Antithrombotic

TreatmentRR

(re

lativ

e ri

sk)

ASA warfarin Plavix® warfarin Plavix® warfarin warfarin + + + + ASA ASA Plavix® Plavix®

+ ASAArch Intern Med 2010;170(16):1433-1441

0.96 1.0

1.45

1.751.91

3.57

4.03

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

None20mg 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 recommendedAge 45-79 years: ASA benefit outweighs GI bleed risk

ASA not recommended

Stroke ASA not recommended<55 years: ASA not recommended55-79 years: ASA if benefit outweighs GI bleed risk

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 CandidatesBased 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 non-preferred

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

% Inhibition Threshold

PRU Threshold

10 259

20 237

30 214

40 187

50 159

60 131

VerifyNow® Results

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 55-63%, 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)

ReferencesRE-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

http://www.mdcalc.com/simplified-pesi-pulmonary-embolism-severity-index/

Documents

Advancements In Anticoagulation June 14, 2013 Dosha Cummins, PharmD, BCPS UAMS Northeast Associate Professor Dept. of Pharmacy Practice Dept. of Family