Hematology Rounds Calgary February 20, 2014 Resolving Controversies in Thrombosis Prevention and Treatment Bill Geerts, MD, FRCPC Director Thromboembolism Program, Sunnybrook HSC Professor of Medicine, University of Toronto National Lead, VTE Prevention, Safer Healthcare Now!
Controversies in Thromboembolism Prevention and Treatment A. Preventing nosocomial VTE - Current thromboprophylaxis - Controversies in prophylaxis - Implementing prophylaxis C. Successfully preventing HIT B. Using DOACs safely
Rationale for Thromboprophylaxis 1. >60% of all VTE is hospitalacquired 2. >450 RCTs of thromboprophylaxis 3. Guidelines have recommended routine thromboprophylaxis since 1986 4. Canadian hospital accreditation standard since 2011
>90% of hospital patients are at risk for VTE All hospitalized patients Hospitalized patients at risk for VTE (95% of patients at Sunnybrook)
Burden of Hospital-Acquired VTE Population of Alberta, 2013 4,025,074 1/1,000/yr Annual VTE rate 4,025 60% Hospital-acquired VTE 2,415/year Most are preventable
Prophylaxis Options 1. Low dose heparin BID or TID 2. Low molecular weight heparin dalteparin (Fragmin ) enoxaparin (Lovenox ) tinzaparin (Innohep ) 3. Fondaparinux (Arixtra ) 4. Oral Factor Xa inhibitors, IIa inhibitors apixaban (Eliquis ) dabigatran (Pradaxa ) rivaroxaban (Xarelto ) 5. Mechanical methods T.E.D. stockings pneumatic compression devices 6. Combinations of anticoagulant and mechanical methods
2014 Thromboprophylaxis Summary Patient Group Options Duration Acute medical illness Surgery: general, gyne, thorac, urol Major orthopedics - THR, TKR - Hip fracture surg LMWH [low dose heparin] LMWH [low dose heparin] rivaroxaban LMWH LMWH High bleeding risk mechanical Discharge Discharge 2-6 weeks 2-6 weeks Until anticoagulant can start
3 Thromboprophylaxis Controversies 1 2 3 Why should LMWH replace S/C heparin? Should LMWH be adjusted at extremes of weight? How long should thromboprophylaxis be given?
1 LMWH SHOULD Replace LDH as thromboprophylaxis LMWH is: 1. More effective than LDH in some patients (stroke, cancer surgery, arthroplasty, trauma) 2. LMWH is once daily vs BID/TID with LDH 3. LMWH virtually eliminates HIT 4. Similar low risk of bleeding 5. Not more costly than heparin (or cheaper)
HIT is 30 times less common with LMWH than LDH Prophylaxis Meta-analysis of prospective studies comparing prophylactic LDH and LMWH Prophylactic anticoagulant HIT Heparin 31/1,223 (2.5%) LMWH 1/1,255 (0.08%) Martel Blood 2005;106:2710
2 LMWH Effect is Weight-Related 19 patients given enoxaparin 40 mg Serial anti-xa testing Frederiksen Br J Surg 2003;90:547
Anti-Xa Levels and Enoxaparin Laparoscopic GBP or banding (~130 kg, BMI ~48) AXa 3-5 hours after 1 st and 3rd dose Anti-Xa level 0.5 0.4 0.3 0.2 0.1 1 st dose 3 rd dose Target AXa = 0.18-0.44 U/mL 0 30 mg BID 40 mg BID 60 mg BID enoxaparin Rowan Obes Surg 2008;18:162 Simone Surg Endosc 2008;22:2292
Weight-Based Thromboprophylaxis Dose should be adjusted at extremes of weight weight enoxaparin dalteparin <40 kg 30 mg daily 2,500 U daily 40-100 kg 40 mg daily or 30 mg BID 5,000 U daily 100-125 kg 40 mg BID 5,000 U BID >125 kg 0.4 mg/kg BID 40 U/kg BID Tinzaparin 4,500 U or 75 U/kg daily
3 Duration of thromboprophylaxis Until ambulating = NO! Until discharge For most medical, surgical patients After discharge THR TKR 2-4 weeks Hip fracture surgery Possibly some cancer surgery patients
Controversies in Thromboembolism Prevention and Treatment A. Preventing nosocomial VTE - Current thromboprophylaxis - Controversies in prophylaxis - Implementing prophylaxis C. Successfully preventing HIT B. Using DOACs safely
12 Local Implementation Steps - 1 1. Institutional commitment (including resources) 2. PLUS multidisciplinary team, committee 3. PLUS local champion / leader 4. PLUS measure baseline performance 5. PLUS written hospital policy on prophylaxis 6. PLUS KISSS principle ( Keep It Simple and Standardize it Smartie )
12 Local Implementation Steps - 2 7. PLUS some education of MDs, RNs, Pharms 8. PLUS mandatory use of order sets with force function (opt out) 9. PLUS empower everyone to be involved docs, nurses, pharmacists ( It s what we do here. ) 10.PLUS measure performance regularly (target = 100% appropriate use) 11.PLUS provide feedback + ongoing QI 12.PLUS monitor hospital-acquired VTE with rootcause analysis ( Was it potentially preventable? )
Appropriate* Prophylaxis by Service Group Service group Total no. patients Prophylaxis indicated Appropriate* prophylaxis ordered 2011 2012 2013 2014 2011 2012 2013 2014 2011 2012 2013 2014 All surgical services All medical services All major ICUs 211 225 242 223 166 171 215 186 86% 88% 93% 96% 221 247 230 210 171 190 177 147 79% 79% 91% 87% 42 44 42 51 33 33 36 42 88% 94% 94% 98% Combined 432 472 462 484 337 361 383 375 281 (83%) 301 (83%) 351 (92%) 347 (93%) *defined as consistent with Sunnybrook policy
Appropriate Prophylaxis* Use in General IM Patients at Sunnybrook 100% 75% Baseline Education, commitment 60% Order sets, audit & feedback 94% 72% 79% 91% 90% 87% 50% 25% 9% 21% 0 2003 2007 2008 2009 2010 2011 2012 2013 2014
Sunnybrook Hospital-Acquired VTE + Root Cause Analysis (2011-13) Identify cases of Hospital-Acquired DVT/PE (during admission or <2 calendar mos after discharge) Symptomatic, proven excl CNS, upr extrem, GI TE service Medical imaging Autopsy Root cause analysis Appropriate* thromboprophylaxis Suboptimal* thromboprophylaxis (=potentially preventable) *according to Sunnybrook s Thromboprophylaxis Policy and Guidelines
Hospital-Acquired DVT/PE 2011-13 (n=150; 5/month) Root cause analysis Appropriate* thromboprophylaxis (104 = 69%) Suboptimal* thromboprophylaxis (=potentially preventable) (46 = 31%)
Hospital-Acquired DVT/PE 2011-13 (n=150; 5/month) Root cause analysis Appropriate* thromboprophylaxis (104 = 69%) Suboptimal* thromboprophylaxis (=potentially preventable) (46 = 31%) Enter into database Real-time feedback Review our VTE P&G Provide feedback to the care team
Hospital-Acquired VTE (2011-13) 2011 (6 mos) 2012 (12 mos) 2013 (12 mos) 2011-13 (30 mos) HA-VTE 22 73 55 150 HA-VTE/mo 3.7 6.1 4.6 5.0 Potentially preventable 9 (41%) 21 (29%) 16 (29%) 46 (31%)
Hosp-Acquired VTE by Clinical Service Overall, 150 HA-VTE July, 2011-Dec, 2013; 31% potentially preventable 30 25 Appropriate thromboprophylaxis Potentially preventable HA-VTE 20 15 10 Ser 1 Ser 2 5 0 Total/service: 2 0 0 0 10 37 14 1 14 1 0 15 0 0 25 1 3 4 1 1 0 15 6
Controversies in Thromboembolism Prevention and Treatment A. Preventing nosocomial VTE - Current thromboprophylaxis - Controversies in prophylaxis - Implementing prophylaxis C. Successfully preventing HIT B. Using DOACs safely
Impact of a Hospital-Wide, Avoid-Heparin Program on: 1. Incidence of HIT 2. Clinical Consequences 3. Resource Use Associated with HIT
Rationale for QI Initiative - 1 At Sunnybrook: 20 HIT cases/year 60% of HIT have HITT Deaths occur Major costs - >$300,000/yr Concern re lawsuits
Rationale for QI Initiative - 2 HIT might be preventable HIT is 5-30 times less likely with LMWH than with UFH The only way to reduce the burden of HIT is to reduce exposure to UFH let s see if we can prevent HIT by replacing most heparin with LMWH
Avoid-Heparin Program Implemented at Sunnybrook HSC in 2006 Small, multidisciplinary committee Reviewed all indications for UFH use Limited discussion with clinical areas (CVS) IV & SC heparin replaced by LMWH for prophylactic & therapeutic indications: UFH removed from arterial & central venous lines Modification of all order sets with removal of UFH and replacement with LMWH Removal of all heparin from most nursing units UFH restricted to intra-operative use in CVS, hemodialysis, and some ACS
Avoid-Heparin Program Coincided with aggressive thromboprophylaxis expansion based on LMWH HIT prevention initiative was not announced Clinicians not aware of a formal QI project and most were not aware of any change No education about HIT No change in investigation of HIT
Annual Incidence of HIT & HITT Patients/10,000 Admissions 14 12 10 8 6 4 2 Avoid-Heparin Transition p<0.001 (pre vs post-intervention phase) 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Year HITT HIT
Annual Incidence of Suspected HIT, Positive HIT ELISA, HIT & HITT Cases/10,000 Admissions 90 80 70 60 50 40 30 20 10 0 18 16 14 42%* 12 10 70%* 8 6 4 81%* 2 0 Patients Suspected with HIT Positive HIT ELISA HIT HITT ELISA HIT Pre-Intervention (2003-2005) Avoid-Heparin (2007-2012) 92%* * p <0.001
Costs of HIT-Care Type of patient Additional costs/case* Before (2003-5) After (2007-12) Cases/yr Cost/yr Cases/yr Costs/yr Suspected HIT negative $119 124 $14,708 100 $11,948 Adjudicated HIT $4,575 10 $45,750 4 $18,300 Adjudicated HITT $34,155 8 $261,855 1 $34,155 TOTAL $322,313 $64,403 $257,910/year *2007 $Cdn Nanwa Pharmacoeconomics 2011;29:511
Controversies in Thromboembolism Prevention and Treatment A. Preventing nosocomial VTE - Current thromboprophylaxis - Controversies in prophylaxis - Implementing prophylaxis C. Successfully preventing HIT B. Using DOACs safely
The novel/new Direct Oral AntiCoagulants (DOACs) apixaban (Eliquis ) dabigatran (Pradaxa ) [ edoxaban (Lixiana ) ] rivaroxaban (Xarelto )
Why is this topic important? DOACs: Direct Oral AntiCoagulants* DOACs are now commonly used, and Their use is increasing Given for life-threatening disorders, and The drugs can be dangerous Most physicians don t know enough much about them hematologists must provide leadership *also called NOACS = New/Novel Oral AntiCoagulants
Approved in Canada Today apixaban dabigatran rivaroxaban Orthopedic prophylaxis Stroke prevention in AF # # # # VTE treatment No No # Other indications No No No Med/surg thromboprophylaxis Mechanical heart valves Cancer, pregnancy, ACS # ODB supported
DOACs: Advantages Property Rapid onset of action Predictable pharmacokinetics Few food, drug interactions No routine lab monitoring Rel. rapid offset of action Relatively inexpensive All of the above Advantages No need for IV/SC anticoag (single, oral drug approach) Given in standard, fixed doses (or limited dose options) Convenient for patients, docs No preop bridging with LMWH Generally affordable Potential for greater/longer use of an anticoagulant fewer thromboemboli, strokes
Key Drug Interactions mechanism apixaban dabigatran rivaroxaban Atorvastatin P-gp competition? 18% No effect Amiodarone P-gp competition? 12-60% Minor effect Verapamil P-gp competition? 12-180% Minor effect Dronedarone P-gp competition? 70-100%? Conazoles Clarithromycin Erythromycin HIV protease inhibitors Rifampin, St.John s Wort, phenytoin, carbamazepine, phenobarbital P-gp competition + CYP3A4 inhib P-gp competition + CYP3A4 inhib P-gp competition + CYP3A4 inhib P-gp + CYP3A4 inducers 100% 140-150% Up to 160%? 15-20% 30-54%? Up to 150% 54% 66% Up to 50% PPI GI absorption? 12-30% No effect Heidbuchel Europace 2013:15:625
NOACs in Atrial Fibrillation Drug Dose Study No. dabigatran (Pradaxa ) 110 mg BID or 150 mg BID RE-LY 18,113 rivaroxaban (Xarelto ) apixaban (Eliquis ) 20 mg BID ROCKET-AF 14,264 5 mg BID ARISTOTLE 18,201
NOACs in Atrial Fibrillation Drug Dose Study No. dabigatran (Pradaxa ) 110 mg BID or 150 mg BID RE-LY 18,113 rivaroxaban (Xarelto ) apixaban (Eliquis ) 20 mg BID ROCKET-AF 14,264 5 mg BID ARISTOTLE 18,201 All 3 NOACs appear to be at least as effective as warfarin All 3 NOACs appear to be at least as safe as warfarin All 3 NOACs were associated with reduced intracranial bleeding
Oral Rivaroxaban after THR/ TKR % 10 8 6 4 2 0 9.4% Risk reduction 55% p<0.001 4.2% enoxaparin (n=6,200) Risk reduction 50% p=0.001 1.0% 0.5% rivaroxaban (n=6,183) P=0.14 0.3% 0.4 % All VTE Symptomatic Major VTE bleeding Turpie Thromb Haemost 2011;105:444
Treatment of DVT/PE: 3 options 1 LMWH S/C warfarin (INR 2.0-3.0) 5-7 d 3 mosindefinite 2 LMWH S/C pregnancy, adenocarcinoma, high bleeding risk? 3 rivaroxaban (Xarelto ) 15 mg PO BID x 3 wks 20 mg daily
Laboratory Monitoring of DOACs Poor correlation between standard coag tests and drug level Major variability in reagent/analyzer Timing of the test is critical 0 24 Assessment of reversal dabigatran rivaroxaban aptt PT (NOT INR) Monitoring of blood level (not yet!) dabigatran rivaroxaban Hemoclot Specific anti-xa
Pre-Procedure Stopping of DOACs (apixaban, dabigatran, rivaroxaban) Renal Function (CrCL, ml/min) Half-life (hours) How far in advance of procedure should NOAC be stopped? 50 10-15 2 days 30 49 15-20 2-3 days <30 * More than 25 4-5 days (check aptt or PT first) * Use of DOAC contra-indicated
Pre -Procedure Use of DOACs DOAC (stop 1-2 days preop if renal function normal) -5-4 -3-2 -1 OR 1 2 3 4 5 6 DAYS
Post -Procedure Use of DOACs Ask yourself: Is it OK that the patient be fully anticoagulated 2 hours after a dose? 1 2 Yes : Restart DOAC at therapeutic doses No : DVT prophylaxis with LMWH or prophylactic dose of DOAC Restart DOAC at therapeutic doses 3 Delay restart of DOAC at therapeutic doses -5-4 -3-2 -1 OR 1 2 3 4 5 6 DAYS
Management of Bleeding on New Oral Anticoagulants 1. No specific antidotes for any 2. No studies of human bleeding reversal (yet)
Management of Bleeding in Patients Always: Receiving a DOAC - 1 Assess the source and severity of bleeding Assess coagulation aptt, PT, platelets - Normal aptt, PT = no significant drug on board Assess renal function + get good urine output Stop the anticoagulant Implement mechanical hemostasis if possible packing, clipping, embolization, surgery [Consider hemodialysis for dabigatran]
Management of Bleeding in Patients Don t use: Receiving a DOAC - 2 Plasma, cryo, vit K unless factor deficiency too Consider: Antifibrinolytics (tranexamic acid) - May help and unlikely to harm a bleeding patient but no data If really desperate : 50 IU/kg for rivaroxaban 1) PCC (Octaplex, Beriplex) II, VII, IX, X 2) FEIBA II, VII, IX, X + activated FVIIa 50-100 IU/kg for dabigatran
Management of Bleeding in Patients Receiving a DOAC - 3 GET HELP! (or a good lawyer) If you re a hematologist, YOU ARE THE HELP! Have and use a local written guideline
Using DOACs Safely Careful selection of patients: good renal function, comorbidity, highly compliant, cost not an issue Know the drugs: pharmacology, findings of main clinical trials Avoid antiplatelet agents unless essential Education of patients, colleagues, primary care Periodic clinical and renal function monitoring
DOACs: Summary apixaban (Eliquis ), dabigatran (Pradaxa ), rivaroxaban (Xarelto ) Effective anticoagulants VTE prophylaxis in TJR, stroke prevention in AF, acute and longer-term VTE treatment Convenient - oral, rapid onset, no lab monitoring Lab - dabigatran (aptt), rivaroxaban (PT) Procedures - stop 1-2 days before (if renal function normal); be careful afterwards
The best DOAC reference by far! Heidbuchel H, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2013;15:625-651.