Updates in Anticoagulation

A. Josh Roberts, Pharm.D., BCPS-AQ CardiologySenior Clinical Pharmacist, UC Davis Medical Center

Associate Clinical Professor, UC San Francisco School of Pharmacy

Associate Clinical Professor, UC Davis School of Medicine

Conflicts of Interest:

NONE

Objectives

• Design a low-dose vitamin K strategy for reversing the effects of warfarin

• Develop a low-molecular weight heparin dosing strategy in dialysis patients

• Design an appropriate DOAC dosing strategy in a dialysis patient

• Devise a short-term treatment strategy for switching from an oral to a parenteral anti-platelet agent

Case #1:BD is a 59yo M with CC of Dark Tarry Stools

ADMIT Dx:• Possible GIB

LABS:• Na 138 | K 4.8 | Cl 102 | Mg 2.0• BUN 13 | SCr 1.13 • INR 7.5• H/H 8.6/25.8 | Plts 210

• prev visit: H/H 10.2/30.6 | Plts 259

VITALS:• BP 106/68 | HR 101

WEIGHT: • Prev Clinic Visit: 128 kg

PMH / PSH:

• Mechanical St Jude Aortic Valve (’14)

• HTN

• CAD s/p 3v-CABG

MEDICATIONS:

• Asa 81 daily

• Carvedilol 25mg BID

• Warfarin as directed

Reversal Strategies

• What do you want out of your reversal agent?

• When do you plan on restarting anticoagulation?

✦ Consider a few days into the future

• Consider level of correction needed

Reversal Strategies

• Time frame for establishing hemostasis?

✦ Minutes - Urgent / Emergent

✦ Hours

✦ Days

• Consider Pharmaco-kinetics + dynamics of medication

• time to onset of action & waning of effect

• Titrate to Effect

✦ Time to procedure?

✦ Visual of bleeding or surrogate lab?

Courtesy of William Dager, Pharm.D.

Vitamin K Route & Dosing

• Onset of Action:

• IV faster than PO

• and cheaper $$

• Vitamin K 2mg IV

• Essentially normalized INR

• 2mg IV – 10mg IV = No Difference

• Larger doses = longer bridgingback to Tx INR

Tsu L. Ann Pharmacother. 2012 Dec;46(12):1617-26

1.

2.

3.

4.

5.

6.

7.

8.

0.25-1.25mg 2-5mg 10mg

INR

Vitamin K (IV)

Low-Dose Strategy

• Small doses (0.25mg - 1mg) IV less likely to over-correct INR

• Vit K 0.25mg - 0.5mg enough?

1.

2.

3.

4.

5.

6.

Baseline 12 Hr 24 Hr 48 Hr

INR

Vit K 0.25 - 1.25mgPO IV

Tsu L. Ann Pharmacother. 2012 Dec;46(12):1617-26

Example:Vitamin K dosing for patients on WARFARIN

Patient’s Daily Warfarin Dose Target INR Goal Bleeding No Bleeding

Low Daily Dose

(< 2mg/day)

2-3 @ 12 hours 0.25mg – 1.25mg IV 1 - 2.5mg PO

1.5 @ 12 hours >/= 2mg IV >/= 5 mg PO

1.5 @ 24 – 48 hours 0.25 – 1.25mg IV >/= 3 mg PO

<1.3 @ 24 – 48 hours* >/= 2mg IV >/= 5 mg PO

Medium Daily Dose

(2 – 4 mg/day)

2-3 @ 12 hours 0.25mg – 1.25mg IV >/= 2 mg PO

1.5 @ 12 hours >/= 2mg IV >/= 5 mg PO

1.5 @ 24 – 48 hours 0.25 – 1.25mg IV >/= 5 mg PO

< 1.3 @ 24 – 48 hours* >/= 2mg IV 5 - 10 mg PO

High Daily Dose

(> 4 mg/day)

2-3 @ 12 hours 0.25mg – 1.25mg IV >/= 2.5 mg PO

1.5 @ 12 hours >/= 2mg IV >/= 5 mg PO

1.5 @ 24 – 48 hours 0.25 – 1.25mg IV >/= 5 mg PO

<1.3 @ 24 – 48 hours* >/= 2mg IV 5 - 10 mg PO

Case #2: BG is a 59yo M with CC of SOB & CP

ADMIT Dx:Bilateral Segmental Pulmonary Embolisms

LABS:• Na 138 | K 4.3 | Cl 102 | Mg 2.2• BUN 63 | SCr 5.13 | BNP 1227• INR 1.09• H/H 9.6/28.8 | Plts 210

VITALS:• BP 127/78 | HR 93

WEIGHT: • Prev Clinic Visit: 92 kg

PMH / PSH:

• Recurrent PEs

• DM2 c/b neuropathy

• CAD

• PAD

• ESRD (HD MWF via HeRO Graft)

MEDICATIONS:

• Asa 81 daily

• Atorvastatin 80 daily

• Aspart Insulin SS

• Metoprolol 50mg BID

• Renal Vitamins daily

• Warfarin as directed

• BG needs a parenteral “bridge” BG back to therapeutic warfarin

• BG is a ‘hard stick’ & now refuses further lab draws

• BG is stable & really wants to go home✦ INR 1.39

• What options do you have…?1. Continue heparin drip2. Switch to Low molecular weight heparin injections

LMWH In Dialysis?

• LMWH is contraindicated in dialysis, right?!

• Many RCTs omitted Dialysis Patients or CrCl <15 ml/min

• Not uncommon in other countries

–Douglas Adams

“Reality is frequently inaccurate.”

LMWH In Dialysis

• No RCT evaluating LMWH & HD

• Case Series + Observational Studies

• LMWH Dosing (IV Prior to Dialytic Session)

• Dalteparin: 39 units/kg

• Enoxaparin: 0.7 mg/kg

• 1mg/kg = ↑ frequency of minor hemorrhaging

0.

0.2

0.4

0.6

0.8

Baseline 2hr 4hr 48hr

Week 1Enoxaparin Dalteparin

0.

0.18

0.35

0.53

0.7

0.88

Baseline 2hr 4hr 48hr

Week 4

Polkinghorne K, et al. Am J Kidney Dis 40:990-995 Saltissi D, et al. Nephrol Dial Transplant (1999) 14: 2698–2703

Enoxaparin & HD: In The Real World

• Enoxaparin 0.7mg/kg SQ DAILY

• Dose range 0.4 - 1 mg/kg

• Rounded to closest whole syringe size

• Indications:

• VTE Treatment (45%)

• AF (13%)

• HD catheter clotting, hypercoagulable state, mech valve, pulm-htn

• No sig diff in Bleeding or Thrombosis

• Use when loss of IV access or extremely hard stick, facilitate discharge, or promote patient compliance

Pon T. Thromb Res. 2014 Jun;133(6):1023-8

Enox(n=82)

UFH(n=82)

p-value

1º Endpoints

Major Bleeding(30day)

Thromboembolicor

HD Catheter Clotting(30day)

2º Endpoints

Hospital LOSMean (±SD)

20 ± 58 29 ± 45 0.02

Mortality(30 Day)

Readmission(30 Day)

Case#3:HK is a 78yo F with CC of Palpitations

ADMIT Dx:AFib + RVR

LABS:• Na 138 | K 4.3 | Cl 102 | Mg 2.2

• BUN 58 | SCr 6.21 | BNP 1227

• INR 1.12

• H/H 9.6/28.8 | Plts 210

VITALS:

• BP 127/82 | HR 134

WEIGHT: • Prev Clinic Visit: 68 kg

PMH / PSH:

• DM2

• HTN

• ESRD (HD TTS via LUE-AVF)

MEDICATIONS:

• Amlodipine 10 daily

• Atorvastatin 80 daily

• Carvedilol 25 BID

• Renal Vitamins 1 tab daily

AgentKinetic Half-Life

>80 ml/min 50-80 ml/min 30-49 ml/min <30 ml/min

Ogata K, et al. J Clin Pharmacol. 2010;50(7):743-53Kaatz S, et al. Am J Heamtol. 2012;87:S141-S145

Dager W, et al. Semin Dial.2015;28(4):354-62

Apixaban & Dialysis

• “No dosage adjustment is recommended… based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis.”

Apixaban Package Insert. https://packageinserts.bms.com/pi/pi_eliquis.pdf (accessed 01/10/18)

DoseCmax

(ng/mL)Cmin

(ng/mL)

Wang X, et al. J Clin Pharmacol. 2016 May;56(5):628-36European Medicines Agency. Apixaban. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/002148/WC500107728.pdf (accessed 01/14/18)

Apixaban & Dialysis

DOAC’s & Dialysis

• CKD-4/5 & Dialysis patients excluded from Phase-3 studies

• Small Pharmacokinetic and -dynamic studies

✦ Single or Two dose administration → Flawed Concept

✦ Does Montecarlo Modeling replace actual human studies?

Single Dose Studies:Dialysis v. Healthy

• Apixaban 5mg

✦ 1st dose before & 2nd dose after HD

✦ “…modest increase (36%) in apixaban AUC and no increase in Cmax…”

• Rivaroxaban 15mg

✦ 1st dose before & 2nd dose after HD

✦ 35% decrease in overall drug clearance

✦ PK/PD “parameters were generally comparable to… patients with moderate-to-severe renal impairment”

Wang X, et al. J Clin Pharmacol. 2016;56(5):628-36Dias C, et al. Am J Nephrol. 2016;43:229-236

DOACsDialysis Patients & The Real World

• Major / Minor Bleeding & Death

• Dabigatran > Rivaroxaban > Warfarin > Aspirin

• Dose-related adverse event outcomes

• Where would apixaban and edoxaban fit?

• Stroke and Systemic Embolism

• too few to draw conclusions

Chan KE, et al. Circulation.2015;131(11):972-9

Rx

Plasma(1st comp)

Tissue (2nd comp)

Deep Tissues(3rd comp)

Eliminated

Adapted: Dager WE. Semin Dial. 2010;23:466-9

↑ exposure = ↑ half-life

Rx

Leve

l

DoseCmax

(ng/mL)Cmin

(ng/mL)

Wang X, et al. J Clin Pharmacol. 2016 May;56(5):628-36European Medicines Agency. Apixaban. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Product_Information/human/002148/WC500107728.pdf (accessed 01/14/18)Mavrakanas T, et al. J Am Soc Nephrol. 2017Jul;28(7):2241-2248

Apixaban & Dialysis

Case#4:PH is a 64yo M with CC of Chest Pain

ADMIT Dx:

NSTEMI

LABS:

• Na 141 | K 3.9 | Cl 105 | Mg 1.9

• BUN 18 | SCr 1.21

• H/H 11.9 / 35.7 | Plts 318

VITALS:

• BP 139/89 | HR 91

WEIGHT:

• Prev Clinic Visit: 107 kg

PMH / PSH:

• CAD

• DESx2 (mLAD, LCx)

• 2 mon prev to current admit

• HTN

• HLD

MEDICATIONS:

• Aspirin 81 daily

• Atorvastatin 40 daily

• Clopidogrel 75 daily

• Lisinopril 20 daily

Available Options Bridging to Surgery

• No available short-acting Oral P2Y12 agents

• Current agents require prolonged hold

• Clopidogrel & Prasugrel: 5 days

• Ticagrelor: 7 days

• Short-acting IV options

• Gp-IIb/IIIa: Eptifibatide, Tirofiban

• P2Y12: Cangrelor

Starting & Stopping in Preparation for Surgery

Renal Function

Cangrelor Tirofiban Eptifibatide

START (after last

PO dose)

DOSE

Normal

Impaired(<30ml/min)

HOLD

Normal

Impaired(<30ml/min)

Angiolillo D, et al. Circulation.2017;136:1955-1975 Angiolillo D, et al. JAMA. 2012;307;265-274

Savonitto S, et al. Br J Anaesth.2010;9:2133-2142 Morici N, et al. Intern Emerg Med.2014;9:225-235

What’s the effect?

FREE FROM…

MACE Bleeding/Transfusion

Cangrelor

Tirofiban

Eptifibatide

Morici N, et al. Intern Emerg Med. 2014;9:225-235

• Systematic Review (9 studies included)✦ 1 RCT (Cangrelor)✦ 5 Observational, Retrospective (4 eptifibatide, 1 tirofiban)✦ 3 Observational, Prospective (3 tirofiban)

Recent “Real World” Experiences

• No need for bolus – “just start the infusion”

• P2y12 receptors already inhibited

• No active coronary events or immediate intervention

• What to do with that aspirin?

• ~60%+ hold

• Outcomes

• Rare MACE & major bleeds

• Few minor bleeds

• Restart Oral Agent

• Reload?

• Maybe – Maybe not…

Walker E, et al. Pharmacotherapy. 2017;37(8):888-892Barra ME, et al. CritPathw Cardiol. 2016;15(3):82-8

Pope H, et al. Crit Care Med. 2016;44:S-199[abstract]Angiolillo D, et al. JAMA. 2012;307;265-274

Considerations

• Time since stent placement• 3 days vs 6 months vs 1 year

• Agent Availability• Varying and/or continued medication shortages• Cost: brand vs generic

• Evidence

• Experience• Novel vs “tried and true”

Questions??