updates in anticoagulation · enoxaparin & hd: in the real world • enoxaparin 0.7mg/kg...
TRANSCRIPT
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??