An#coagulant Choices in Renal
Impairment
Karen Shalansky, Pharm.D.
Pharmacotherapeu#c Specialist, Nephrology Vancouver General Hospital
Clinical Professor
Faculty of Pharmaceu#cal Sciences, UBC
karen.shalansky@vch.ca
April 18, 2012
Disclosures
I have no known or real conflicts
of interest to declare
Outline
•
Review mechanisms of ac0on of an0coagulants
•
Compare the new oral an0coagulants
• dabigatran, rivaroxaban, apixaban
•
Discuss an0coagulant op0ons in renal impairment
•
Focus on LMWH use in renal impairment
–
Role of an0-‐Xa monitoring
–
cases with clinical use of LMWH in dialysis
• Long-‐term 0nzaparin and an0-‐Xa levels
• Triple an0coagulant therapy
• Bridge Therapy
Fibrin Clot XII VII VIII IX XI
II
V
X
I
Unfrac#onated Heparin Warfarin Low Molecular Weight Heparin
An#coagulant Sites of Ac#on
Direct Thrombin (IIa) Inhibitors -‐ dabigatran, argatroban
Factor Xa Inhibitors –
rivaroxaban, apixaban, fondaparinux
Dabigatran etexilate Rivaroxaban Apixaban
Target Inhibi#on Both free and clot bound Factor IIa (Thrombin) Factor Xa Factor Xa
Coag Assay* aPTT (2-‐3x); Thrombin #me (27x)
↑ INR 40% Xa inhibi0on (68%) ↑ aPTT 40%; ↑ INR 40% Xa inhibi0on ↑ aPTT; ↑ INR Oral Bioavailabilty 6-‐7% 60-‐80% 50% T (max) 1-‐3 h 2-‐4 h 1-‐3 h Half-‐life 14-‐17 h 9-‐13 h 8-‐15 h Metabolism /
Elimina#on 20% biliary 80% renal
66% renal (36% unchanged)
33% biliary
25% renal 75% biliary
Dialyzable Yes No (92-‐95% PB) Unlikely (87% PB)
Hold Prior to Surgery
eGFR > 50 mL/min Minor surgery: 1 day Major surgery: 3 days
Minor surgery : 1 day
Major surgery: 2 days Rivaroxaban ? Similar to
CYP Metabolism No 30% CYP3A4 15% CYP3A4
P-‐glycoprotein
Substrate Yes Yes Yes
Compara#ve Features of New Oral An#coagulants
P-‐Glycoprotein Drug Interac#ons with NOA
• P-‐glycoprotein (P-‐gp) is a transport protein that func0ons as an
efflux pump to prevent absorp0on of certain drugs, including the new oral an0coagulants
• Inhibitors of P-‐gp – increase absorp0on of NOA
Azole antifungals* Ritonavir* amiodarone verapamil quinidine cyclosporin tacrolimus Clarithro/Erythro* Inhibitors Rifampin** Phenytoin** Carbamazepine** Phenobarbital** Dexamethasone Doxorubicin St. John’s Wort** Inducers
New Oral An#coagulant (NOA) Trials
Dabigatran Rivaroxaban Apixaban
Orthopedic Prophylaxis
(Total Hip and Knee Replacement)
ü
RE-‐MOBILIZE RE-‐MODEL RE-‐NOVATE
ü
RECORD 1 RECORD 2 RECORD 3 RECORD 4
ü
ADVANCE 1 ADVANCE 2 ADVANCE 3
Stroke preven0on in
Atrial Fibrilla0on RE-‐LY (W)
ü
ROCKET AF (W)
ü
AVERROES (ASA) ARISTOTLE (W)
VTE Treatment RECOVER REMEDY
EINSTEIN PE EINSTEIN DVT EINSTEIN-‐EXT
AMPLIFY AMPLIFY-‐EXT
Canadian Dosing Guidelines for NOA
Dabigatran Rivaroxaban Apixaban
Orthopedic Prophylaxis (TKR = x 14 days; THR = x 35 days)
> 50 mL/min 220 mg daily 10 mg daily 2.5 mg BID
30-‐50 mL/min 150 mg daily 10 mg daily (Cau0on) 2.5 mg BID
15-‐29 mL/ min Avoid (black box) Avoid 2.5 mg BID (AUC ↑ 44%) (Cau0on)
< 15 mL/min Avoid Avoid Avoid
Stroke Preven#on in Atrial Fibrilla#on
> 50 mL/min 150 mg BID 20 mg daily
30-‐50 mL/min
150 mg BID
(if ≥ 75 yrs + risk factor for bleeding, consider 110 mg BID)
15 mg daily
Advantages of New Oral An#coagulants
•
Fixed dosing
•
Monitoring of an0coagulant effect not
required
Limita#ons of New Oral An#coagulants
• Inability to Measure an0coagulant effect
– Poten0al for increased risk of stroke or embolism if poor compliance
– Poten0al for increased risk of bleed if reduced renal func0on/DI
(Dabigatran -‐ 260 fatal bleeding events worldwide Mar 08 to Oct 11)
• Lack of specific an0dote
– Prothrombin complex concentrate (Octaplex®) for intracranial hemorrhage
(Octaplex® – plasma derived, purified Factors II, VII, IX, X, protein C and S)
• Some drug interac0ons
– p-‐glycoprotein inhibitors/inducers
• Dose adjustments required in renal dysfunc0on
– Should not be prescribed for eGFR < 30 mL/min (BLACK BOX for dabigatran)
• Cost
– Rivaroxaban covered for orthopedic prophylaxis
An#coagulant Op#ons in Renal Failure
•
Drugs with no significant renal clearance
– Unfrac0onated heparin (UFH)
– Warfarin
– Direct Thrombin Inhibitors: argatroban
– Direct Factor Xa inhibitors: apixaban (avoid < 15 mL/min)
•
Drugs with significant dependence on renal clearance
– Low molecular weight heparins (LMWHs)
– Factor Xa inhibitors:
• Indirect -‐ Pentasaccharide: fondaparinux
• Direct – rivaroxaban
– Heparinoids: danaparoid
Factor Xa Inhibitors
Indirect Inhibitors
• Fondaparinux • IdraparinuxDirect Inhibitors
• Rivaroxaban • Apixaban • Edoxaban • Betrixaban FONDFondaparinux
•
Regional Approval
–
Unstable angina/non-‐STEMI (2.5 mg SC daily)
–
Management of HIT
• Tx VTE: 5-‐10 mg SC daily; Prophylaxis VTE: 2.5 mg SC daily
• Easier to administer vs argatroban (con0nuous infusion)
•
Elimina0on
–
t/12 = 17-‐21 hrs; Elimina0on = 77% unchanged urine
•
Renal Dosing (hemodialysis) – case reports
–
Tx VTE: 2.5 mg SC every 2 days (monitor an0-‐Xa levels
3 h peak 0.5-‐1.5; trough < 0.5)
• Give dose ater dialysis
2012 ACCP Guidelines
•
Appropriate dose of LMWH in pa0ents with severe
renal insufficiency (< 30 mL/min) is uncertain
•
Clearance of the an#-‐Xa effect of LMWH correlates
with CrCl (enoxaparin, nadroparin, dalteparin)
– Excep#on: Tinzaparin not shown to correlate with CrCl
•
If severe renal insufficiency and therapeu0c
an0coagula0on required, suggest UFH over LMWH
•
If LMWH is used in pa0ents with severe renal
insufficiency for therapeu0c an0coagula0on,
suggest monitor an0-‐Xa levels
Measure in pa0ents with renal failue (CrCl < 30
mL/min) or obesity
•
Measure peak effect (4 hours)
–
3-‐4 hours ater twice daily dosing
–
4-‐5 hours ater once daily dosing
–
Twice daily:
0.6-‐1
units/mL
–
Once daily:
1-‐2
units/mL (Tinzaparin 0.6-‐1.5 U/mL*)
•
Trough levels
< 0.5
units/mL
An#-‐Xa Monitoring
(not an exact science)
Mean Peak An#-‐Xa Levels
(Normal Renal Func0on)
(Semin Thromb Hemost 2001;27:519-22)
Heparin and LMWHs
• Pentasaccharide
sequence binds to AT and accelerates its inhibitory ac0vity • Factor Xa – requires
only pentasaccharide • Thrombin – requires
18 saccharide units • LMWHs have less
ac0vity against
thrombin as longer chain length required
Clearance of UFH and LMWHs
• Higher MW chains are cleared by dose-‐dependent hepa0c
mechanism
• Lower MW chains are cleared by dose-‐independent renal
route
Agent
Average MW (daltons) An0Xa:IIa Ra0o
UFH 15,000 1:1 Tinzaparin 6,500 1.9:1 Dalteparin 5,600 2.0 – 2.7:1 Enoxaparin 4,500 2.7 – 4.1:1 Nadroparin 4,300 3.2 – 3.7:1 (Pharmacotherapy 2001;21:218-‐34; Pharmacotherapy 2005; 25:881-‐5)
Tinzaparin
•
Highest MW –may be less dependent upon renal
clearance
•
Closest an0-‐Xa:IIa ac0vity compared to heparin
Agent
Average MW
(daltons)
An#Xa:IIa
Ra#o
Dose Adjustment
CrCl < 30 mL/min
Heparin 15,000 1:1 No
Tinzaparin 6500 1.9:1 No (short-‐term)
Dalteparin 5600 2.0-‐2.7:1 ?
Enoxaparin 4500 2.7-‐4.1:1 Yes (50% -‐ per CPS) Nadroparin 4300 3.2-‐3.7:1 Yes (no guidelines)
Tinzaparin Full Dose
(175 units/kg/day)
Trial Popula#on Dura#on Outcome
Drug Safety
2002:25:725-‐33 200 elderly VTEpts ~25% Cr Cl 20-‐35 mL/min
Up to 30 d
(mean 19 d) 88% peaks < 1.5 U/mL (Day 1, qweek) -‐ No correla0on to CrCl Thromb Haemost 2000;84: 800-‐4 30 elderly VTE pts ~25% CrCl 20-‐29 mL/min
10 days All peaks < 1.1 U/mL (Days 1, 2, 7, 10)
-‐ No correla0on to CrCl Blood 2006; 108:884 (abstract) 78 pts with VTE and varying CrCl including HD
5-‐7 days 94% troughs < 0.5 U/mL (Days 3, 5, 7)
-‐No correla0on to CrCl Thromb Res 2011;128:27-‐34 (IRIS) MC, OL, R cf UFH 539 elderly with DVT and CKD (25% pts with CrCl< 30 mL/min) 5-‐10 days, then warfarin (f/ u = 90 d)
-‐ Study stopped early due to
↑ mortality in Tinza arm at day
28 (11.9% vs 6.3%, p=0.035) -‐ CA, sepsis in pts ≥ 90 yrs -‐
Enoxaparin Dose Adjustment
•
Linear correla0on between an0-‐Xa levels and CrCl
– Prolonged t1/2 (2.94 vs 5.12 hrs CrCl 5-‐21 mL/min)
•
CPS dose adjustment for CrCl < 30 mL/min
– Treatment: 1 mg/kg SC Q24H
– Prophylaxis: 30 mg SC Q24H
•
Poten0ally low peak and trough levels (up to 26%)
(Pharmacother 2007;27:1347; Thromb Res 2005;116;41)
•
Pharmacokine0c trials
– Treatment: 0.5-‐0.75 mg/kg Q12H (Am Heart J 2004;148:582)
Case 1. Long-‐Term Tinzaparin
A case of Calciphylaxis
and Atrial Fibrilla#on
Case 1. Calciphylaxis and A Fib
•
79 yo female, 75 kg admiyed with calciphylaxis
& atrial fibrilla0on
–
D/C warfarin, daily HD (5/7), hyperbaric unit,
sodium thiosulphate, lanthanum
–
Started on 0nzaparin 14,000 units SC daily
(75 kg x 175 units/kg = 13, 125 units)
Peak An#-‐Xa levels (6h):
• Day 3 = 0.85 units/mL
• Day 16 = 0.88 units/mL
• Day 37 = 0.78 units/mL
Case 2. Long-‐Term Tinzaparin and
Triple An#coagulant Therapy
A case of An#-‐phospholipid
syndrome and MI
Case 2: 73 yo female, 80kg on HD
Date Event Tinzaparin Dose (SC)
Oct-‐06 to
Aug-‐07 Start HD 14,000 U (Aug 23/07 peak an0-‐Xa level = 1.03 U/mL) → 10,000 U → 7000 U daily Aug-‐09 Seizure (admission) 7000 units daily
+ Levateracetam (Keppra®)
Aug-‐09 Pneumonia-‐ICU NSTEMI x 2
7000 units SC daily
+ ASA 81mg PO daily + Clopidogrel 75 mg PO daily
Dec-‐09 Let upper arm
hematoma ASA + Plavix held; Discharged Jan-‐10 to RN home on triple therapy above Feb-‐10 Right upper arm
hematoma (readmit); Heme consult
D/C Tinzaparin and Clopidogrel
ASA 81mg daily + Heparin 5000 units SC BID
Sept-‐10 Humerus # -‐ fall Deceased (?PE vs sudden cardiac death)
PMH: An0phospholipid an0body syndrome (DVT/PE 2000, IVC filter, warfarin failure, a fib) → Lifelong 0nzaparin
Bleed Risk from Single, Dual, or Triple
Therapy in Pa#ents with A Fib
Variable RR (95% CI) non-‐ fatal bleed Warfarin 1 (reference) Crude Rate = 3.6% Aspirin 0.84 (0.8-‐0.89) Clopidogrel 0.94 (0.76-‐1.16) ASA +C 1.64 (1.33-‐2.03) W+ASA 1.77 (1.66-‐1.90) W+C 3.16 (2.48-‐4.03) W+C+ASA 3.93 (3.05-‐5.05)
(Arch Int Med 2010;170:1433-‐41)
• Na0onwide Danish registry of
82,854 pa0ents with atrial fib discharged on warfarin, ASA, or clopidogrel (Jan 97-‐Dec 06)
• Analyzed risk hospitaliza0on or
death due to bleeding
• 12,191 (10.3%) had non-‐fatal
Major Bleeding in HD Pa#ents
• Retrospec0ve review of 255 pts from Jan 2002-‐Jan 2004
(1028 person years of exposure)
• 25/26 major bleeds were upper or lower GI bleed; 1 = CNS
Treatment # pts Major
Bleed % Major Bleeds Hazard Model for Time to First Bleed (95% CI)
None 178 4 0.8% Reference Warfarin 89 15 3.1% 3.9 (1.05-‐14.6) ASA 107 12 4.4% 5.8 (1.9-‐18.0) ASA + Warfarin 50 5 6.3% 8.2 (2.2-‐30.7) Total 255 26 (CJASN 2008;3:105-‐110)
Cases 3 & 4 Bridge Therapy
Peri-‐opera#ve Risk Stra#fica#on
(Chest 2012;141:326s-‐350s)
Thrombosis
Risk Mechanical Heart Valve Atrial Fibrilla#on VTE Bridge
HIGH • Mitral Valve
• Older aor0c
valve (0l0ng disc) • Recent (< 6 mo) stroke or TIA
• CHADS2 5-‐6 • Recent (< 3 mo) stroke or TIA • Rheuma0c valvular HD • VTE < 3 mo • Severe thrombophilia Yes (2C)
MODERATE • Bileaflet aor0c
valve + one of: a fib, stroke, TIA, HT, DM, CHF, > 75 • CHADS2 3-‐4 • VTE 3-‐12 mo • Recurrent VTE • Ac0ve cancer
Full dose or Prophylac0c dose or No bridge
LOW • Bileaflet aor0c
valve & no risk factors for stroke
• CHADS2 0-‐2 • VTE > 12 mos and no other risk factors
How to Bridge with LMWH
(Circula#on 2004;110:1658-‐63; Chest 2012;141:326s-‐350s)Day
-‐ 5 Day -‐ 3 Day -‐ 1 Day 0 +1 to +3 Day
Full dose OD or BID or prophylactic dose OD
No dose within 24 h (or ½ dose in am); INR >1.5 Vit K 1mg po Restart depends on adequate hemostasis Stop Warf Stop LMWH am / pm Start LMWH Start Warf 12-‐24h post-‐sx Start LMWH am / pm Stop LMWH when INR therapeu#c
Temporary Discon#nua#on of Warfarin:
INR Decay with Target Range 2-‐3
Mean INR 1.6 Mean INR 2.6 Mean INR 1.1 Hours 20 40 60 80 100 120 140 160 180 Age > 55 yrs Age ≤ 55 yrs INR Hours Mean INR 1.6 Mean INR 2.6 Mean INR 1.1 20 40 60 80 120 140 160 180 1 2 3 4 0
• N= 22 pa0ents; serial INRs done at 2.7 and 4.7 days ater D/C
Case 3: 72 yo, 91 kg male
•
Recent bilateral PE July 4/11; Hx of PE and DVT x 2
•
Pt had been off warfarin AMA prior to recent event
•
Requires fistuloplasty July 19/11
Date Day Action
July 14 Day - 5 Stop Warfarin (INR = 2.7)
July 15-17 Day - 4 to - 2
(low dose ID heparin)
Start Tinzaparin 14,000 units qpm (175 units x 91kg = 15,925 units)
July 18 Day - 1 No Tinzaparin; INR = 1.0
July 19 Day 0 (if okay by
vascular)
Restart Warfarin in evening Restart Tinzaparin in evening
July 27 Day + 8 (end of 10 day
Pharmacare coverage)
Case 4: Accidental Overdose
Date Event Tinzaparin Dose
Aug 6 Discharged INR = 1.2 10,000 units daily
Aug 7-9 Patient error with dose; was
dispensed 3 x 20,000 unit/2 mL vial (instead of 10,000 unit syringe)
20,000 units daily x 3
Aug 10 Ran out of Tinzaparin None
Aug 11 INR = 1.3; error discovered;
Anti-Xa level ordered (43 h post)
5000 units
•
74 yo, 58 kg male with PE July 27/10;
•
Hx of pulmonary fibrosis
Aug 12 Anti-Xa Level = 0.26 units/mL 10,000 units
Case 5. LMWH Prophylaxis
A paraplegic pa0ent
Dalteparin Prophylaxis Trial:
DIRECT
(Arch Intern Med 2008;168:1805-‐12)
•
138 ICU pa0ents, CrCl < 30mL/min (mean 18.9mL/min)
– 9.4% on dialysis
•
Dalteparin 5000 U SC daily < 30 days (median 7 days;
IQR 4-‐12 days)
•
Trough an0-‐Xa levels on days 3, 10, 17
Results:
•
All trough an0-‐Xa levels < 0.4 units/mL
•
No evidence of accumula0on
•
DVT = 5.1%
•
Major bleeding = 7.2%
VTE Prophylaxis Guidelines: VCH/PHC
•
Dalteparin 5000 units SC daily (eGFR > 10 mL/min)
– If pa0ent has eGFR 10-‐30 mL/min and therapy to extend
beyond 10 days, consider switch to heparin Q12H
•
Heparin 5000 units SC Q12h (eGFR < 10 mL/min)
Weight Range Dalteparin
(eGFR > 10mL/min )
Heparin (eGFR < 10 mL/min)
40 kg or less 2500 units SC daily 2500 units SC Q12H
41 kg to BMI 40 kg/m2 5000 units SC daily 5000 units SC Q12H
Case 5: Dalteparin Prophylaxis
Date Event Anticoagulation
Apr 2, 2010
Admitted for ↓ LOC – ICU intubation x 2 weeks
CKD 2° diabetic nephropathy
Heparin 5000 units SC Q8H
Apr 22 Dialysis initiated – R IJ inserted - radiologist noted incidental
finding of R IJ vein thrombosis (from previous ICU catheter)
Heparin 5000 units SC Q8H
May 1 Heme consult
Doppler R neck negative
Dalteparin 5000 units SC daily
•
57 yo male, 95 kg, paraplegic
June 2 Anti-Xa Level > 2 units/mL (13 h post dose)
Hold x 24 h, then
Dalteparin 2500 U SC OD June 5 Patient discharged
Conclusion – An#coagulant Choices in
Renal Impairment (eGFR < 30 mL/min)
•
VTE Treatment
– Unfrac0onated heparin IV preferred in hospital
– LMWH (monitor an0-‐Xa levels with long-‐term therapy)
• Tinzaparin – full dose (up to 10d)
• Enoxaparin – 1/2 dose (1 mg/kg SC daily)
•
VTE Prophylaxis
– Heparin 5000 units SC Q8-‐12H
– Apixaban – Avoid < 15 mL/min
– LMWH
• Tinzaparin – no dose restric0ons
• Dalteparin – 5000 units SC OD up to 10 days (↓2500 units if low risk) • Enoxaparin – 30 mg SC daily (1/2 dose)