Anticoagulation Update: DOACs, VTE Guidelines, Bridging and icentra (whew!) Scott C. Woller, MD Co Director, Thrombosis Program Intermountain Medical Center Professor of Medicine University of Utah School of Medicine Clinical Learning Day 2016
Disclosures Investigator initiated grant recipient: Bristol Myers Squibb (paid to Intermountain Healthcare) Panelist American College of Chest Physicians (ACCP) Clinical Practice Guideline: Antithrombotic therapy for venous thromboembolic disease (AT10)
Objectives DOAC limitations & use in routine clinical care Special populations AT10 Updates: Venous Thromboembolism Anticoagulation procedural interruption ( bridging ) Warfarin DOACs Why & how to manage anticoagulation in icentra
The Direct Oral Anticoagulants
The Direct Oral Anticoagulants Rivaroxaban Apixaban Edoxaban Dabigatran BRAND NAME PHARMACEUTICAL Xarleto Bayer Eliquis BMS & Pfizer Savaysa Daiichi Sankyo Pradaxa Boehringer Ingelheim TARGET Factor Xa Factor Xa Factor Xa Factor IIa BIOAVAILABILITY (%) ~80 ~50 62 6 7 TIME TO PEAK (h) 2 3 1 2 1 2 1.5 HALF LIFE (h) 9 13 8 15 9 10 12 14 RENAL EXCRETION (%) 33 25 35 >80 EFFECT ON aptt/pt* 1.8/2.6 1.2/~2 yes 2.3/NR EFFECT ON Xa 68% NR NR No Effect DRUG INTERACTIONS CYP3A4 IND/INH CYP3A4 INH P gp INH/CYP3A4 Verapamil/rifampin Derived from: Crowther. Blood. 2008;111:4871-4879; Garcia, D. Blood. 2010;115:15-20; http://www.eliquis.com/pdf/eliquis%20%c2%ae%20(apixaban)%20smpc.pdf Schulman Thromb Haemost 2014; 111:
Choosing a DOAC vs. warfarin in AF Ruff CT et al. Lancet 2014; 383: 955 62
Choosing a DOAC vs. warfarin in AF * *TTR > 66% Ruff CT et al. Lancet 2014; 383: 955 62
AT10 Summary of evidence: Recurrent VTE QUESTION: Should a DOAC or warfarin be used for acute and long term treatment of VTE? NOAC n (studies) RIVAROXABAN 8281 (2 studies) DABIGATRAN 5107 (2 studies) APIXABAN 5244 (1 study) EDOXABAN 8240 (1 study) Quality assessment Risk of bias Overall quality of evidence no serious risk of bias no serious risk of bias no serious risk of bias no serious risk of bias MODERATE due to imprecision MODERATE due to imprecision MODERATE due to imprecision MODERATE due to imprecision Summary of Findings Study event rates (%) Relative Anticipated absolute effects With LMWH With NOAC effect Risk w/ Risk difference and VKA (95% CI) LMWH with NOACs &VKA (95% CI) Recurrent VTE 95/4131 (2.3%) 86/4150 (2.1%) 55/2554 (2.2%) 2 60/2553 (2.4%) 71/2635 (2.7%) 59/2609 (2.3%) 146/4122 (3.5%) 3 130/4118 (3.2%) RR 0.90 (0.68 to 1.2) RR 1.12 (0.77 to 1.62) RR 0.84 (0.6 to 1.18) RR 0.83 (0.57 to 1.21) 23 per 1000 2 fewer per 1000 (from 7 fewer to 5 more) 22 per 1000 3 more per 1000 (from 5 fewer to 13 more) 27 per 1000 4 fewer per 1000 (from 11 fewer to 5 more) 35 per 1000 6 fewer per 1000 (from 15 fewer to 7 more)
Who is a candidate for a DOAC therapy to treat VTE? Who is not? From the clinical trials: Need for thrombolytic therapy An indication for anticoagulation for which no DOAC approval exists High risk of bleeding Significant liver disease (hepatitis, cirrhosis, or AST/ALT 3x ULN) Creatinine clearance 30 ml/min (apixaban threshold was 25 ml/min) Aspirin use (100 mg/day) Concomitant use of interacting medications Uncontrolled hypertension Schulman S (2013) N Engl J Med 368:709 718. EINSTEIN Investigators (2010) N Engl J Med 363:2499 2510. Agnelli G (2013) N Engl J Med 368:699 708. Schulman S (2009) N Engl J Med 361:2342 2352. Schulman S (2014) Circulation 129:764 772 EINSTEIN PE Investigators (2012). N Engl J Med 366:1287 1297. Agnelli G (2013) N Engl J Med 369:799 808. Hokusai VTE Investigators (2013) N Engl J Med 369:1406 1415.
Who is a candidate for a DOAC therapy to treat VTE? Who is not? From the school of hard knocks: Patients who struggle with compliance (unless related to transportation for INRs) Warfarin is likely favorable to allow ascertainment of and anticoagulant effect Financial barriers to longitudinal compliance After 1.1 year f/u <50% prescribed DOAC picked up adequate drug to cover 80% days Kearon C AT10 Chest 2016; Yao, X Chest Physician Vol. 11, No. 2 Feb. 2016
DOAC therapy: Special populations
Candidates for a DOAC therapy: Special populations Pregnancy + Dabigatran or rivaroxaban = Apixaban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies Ex vivo drug concentration across placenta F:M ratio 0.9 Edoxaban animal studies demonstrated no fetal harm DOAC excretion in breast milk is not known. XARELTO PM ENG 10JUL2014 172618.pdf. http://www.bayer Boehringer Ingelheim Canada Ltd (2014) Pradaxa product monograph. http://www.boehringeringelheim.ca; images from: colorbox.com; dailykos.com; Bapat P et al.. J Thromb Haemost 2016; 14: 1436 41.; Bapat P etal. Obstet Gynecol 2014; 123: 1256; 15 Bapat P etal. Am J Obstet Gynecol 2015; 213: 710.e1 6.
Candidates for a DOAC therapy: Special populations Pregnancy dailykos.com
Candidates for a DOAC therapy: Special populations Extremes of weight Evidence is limited Patients <50 60 kg were 2 13 % of DOAC study populations & 16 % of patients were >100 kg 1 meta analysis showed that for patients >100kg recurrent VTE risk was 0.9 (95% CI 0.77 1.06) Dabigatran does not appear to be affected by extremes of weight Weight may affect kinetics of anti Xa s but the clinical significance is unknown. ISTH and AC Forum suggest against use based on PK/PD in obese Schulman NEJM 2009; EINSTEIN Investigators NEJM 2010; AMPLIFY NEJM 2013; HOKUSAI NEJM 2013; Stangier DJ Clin Pharmacokinet 2008; Frost J. thromb Haemost 2009; Upreti VV 2013 Br J Clin Pharmacol; Kubitza D 2007 J Clin Pharmacol; clipartbest.com; van Es Blood. 2014; Martin K etal. J Thromb Haemost 2016; 14: 1308 13.; Burnett etal. J Thromb Thrombolysis (2016) 41:206 232
Candidates for a DOAC therapy: Special populations Extremes of weight dailykos.com
Candidates for a DOAC therapy: Special populations Elderly Evidence from a meta analysis of the Phase 3 trials studying VTE Pooled DOAC vs. VKA for age 75 years for recurrent VTE or VTE related death: HR 0.56 (95% CI 0.38 0.82) p=0.003 Pooled DOAC vs. VKA for age 75 years for Major bleeding: HR 0.49 (95% CI 0.25 0.96) p=0.04 van Es N. Blood. 2014; pintrest.com
Candidates for a DOAC therapy: Special populations Elderly van Es N. Blood. 2014; pintrest.com
Candidates for a DOAC therapy: Special populations Thrombophilias Evidence is limited Patients with thrombophilias comprised 2 18% of those enrolled in DOAC trials Post hoc dabigatran data shows no difference in recurrent VTE Exception: APS 3 ongoing studies RAPS (Canada), TRAPS (Italy), ASTRO APS (USA) Schulman S (2013) N Engl J Med 368:709 718. EINSTEIN Investigators (2010) N Engl J Med 363:2499 2510. Agnelli G (2013) N Engl J Med 368:699 708. Schulman S (2009) N Engl J Med 361:2342 2352. Schulman S (2014) Circulation 129:764 772 EINSTEIN PE Investigators (2012). N Engl J Med 366:1287 1297. Agnelli G (2013) N Engl J Med 369:799 808. Hokusai VTE Investigators (2013) N Engl J Med 369:1406 1415; Schulman S et al (2014) ASH 56th annual meeting Dec 2014, session 332 abstract 1544
Candidates for a DOAC therapy: Special populations Thrombophilias dailykos.com
Candidates for a DOAC therapy: Special populations Thrombophilias APS = dailykos.com
Candidates for a DOAC therapy: Special populations Cancer No dedicated RCT evidence for cancer patients exists Systematic reviews of the cancer subgroup from the clinical trials suggest DOACs are similar to VKA for VTE recurrence risk reduction and no difference in MB/CRNMB 1 meta analysis suggested for VTE recurrence RR 0.57 (95% CI 0.36 0.91; p=0.02) Schulman S 2013 NEJM EINSTEIN Investigators 2010 NEJM ; Agnelli G 2013 NEJM; Schulman S 2009 NEJM; Schulman S 2014 Circulation; EINSTEIN PE Investigators 2012 NEJM; Agnelli G 2013 NEJM; Hokusai VTE Investigators 2013 NEJM; Castellucci LA. 2014 JAMA; Carrier M. 2014 Thromb Res; Vedovati MC. 2015 Chest; Di Minno MN. 2014 J Thromb Haemost; Franchini M.2015 Thromb Res
Candidates for a DOAC therapy: Special populations Cancer Schulman S 2013 NEJM EINSTEIN Investigators 2010 NEJM ; Agnelli G 2013 NEJM; Schulman S 2009 NEJM; Schulman S 2014 Circulation; EINSTEIN PE Investigators 2012 NEJM; Agnelli G 2013 NEJM; Hokusai VTE Investigators 2013 NEJM; Castellucci LA. 2014 JAMA; Carrier M. 2014 Thromb Res; Vedovati MC. 2015 Chest; Di Minno MN. 2014 J Thromb Haemost; Franchini M.2015 Thromb Res; va Es 2015; Kearon C AT10 2016
Candidates for a DOAC therapy: Special populations Cancer AT10 states that For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). No comparison of DOAC with LMWH to date 5 ongoing trials (rivaroxaban=2, apixaban=2, edoxaban=1) clinicaltrials.gov accessed 12 MAR 2016 Kearon C AT10 2016
Candidates for a DOAC therapy: Special populations Cancer dailykos.com
Choosing between DOACs: Summary Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Cost +++ + + + + Compliance +++ + ++ + ++ Bleeding risk Renal Dysfunction + ++ ++ +++ +++ +++ + + ++ + QOL + ++ +++ ++ +++ +: Less favorable +++: More favorable
Treatment updates for Venous Thromboembolism Kearon C. CHEST 2016; 149(2):315-352
AT living guideline model Of the 53 recommendations in this update, 20 (38%) are strong recommendations (Grade 1) and none are based Evaluation of Individuals with Pulmonary Nodules: General Approach on high quality (Grade A) evidence. AT LGM represents the first endeavor to transition to a continually updated Living Guideline with a format designed to facilitate updates as new evidence becomes available.
AT10 Choice of anticoagulant for long term treatment of DVT and PE: DOAC vs. warfarin AT10 Guideline Statement: Evaluation of Individuals with Pulmonary Nodules: General Approach In patients with DVT of the leg or PE and no cancer, as long term (first 3 months) anticoagulant therapy, we suggest apixaban or edoxaban or rivaroxaban or dabigatran over VKA therapy (Grade 2B). Remarks: Acute therapy with parenteral anticoagulation is given before dabigatran and edoxaban. For the first time an alternative to usual care with low molecular weight heparin and warfarin has been suggested for the long term treatment of PE and DVT. Kearon C. Chest. 2016. doi:10.1016/j.chest.2015.11.026
AT10 Choice of anticoagulant for long term treatment of DVT and PE: DOAC vs. warfarin Recommended therapy for VTE takes into consideration efficacy, Evaluation of Individuals with Pulmonary Nodules: General Approach safety, and burden of treatment (can also include cost). Is there evidence to recommend 1 DOAC over another? DOACs have not been compared head to head for patientimportant outcomes. Based on indirect comparisons these outcomes appear to be similar with all of the NOACs Individual patient characteristics (including cost and insurance coverage) will likely drive choice of anticoagulant for the initial 3 months of therapy
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! AT10 Guideline Statement: In patients with subsegmental PE (no involvement of more proximal pulmonary arteries), no proximal DVT in the legs, and a low risk for recurrent VTE (see text), we suggest clinical surveillance over anticoagulation (Grade 2C). Kearon C. CHEST 2016; 149(2):315-352
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! Definition: Evaluation Subsegmental of Individuals PE with (SSPE) Pulmonary refers Nodules: to PE that General is confined Approach to the subsegmental pulmonary arteries (and may occur bilaterally). SSPE has become important because improvements in computerized tomography pulmonary angiography (CTPA) have increased how often subsegmental PE is diagnosed. Now SSPE constitutes about 10% of all PE cases.
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! Evaluation of Individuals with Pulmonary Nodules: General Approach No RCTs exist to direct treatment of SSPE however high quality evidence supports anticoagulation for treatment of larger PE Whether the risk of progressive or recurrent VTE is high enough to justify anticoagulation in patients with SSPE is uncertain
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! What considerations are important upon weighing SSPE treatment options? Evaluation of Individuals with Pulmonary Nodules: General Approach 1. Consider certainty of true thrombosis being present (evaluate likelihood of observed thrombosis being a false positive result) SSPE is more likely a true positive if CTPA characteristics (quality, multiple defects, multiple projections, etc.) Patients are symptomatic (as opposed to PE being an incidental finding) There is a high clinical pre test probability for PE Elevated D Dimer that s otherwise unexplained
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! What considerations are important upon weighing SSPE treatment options? Evaluation of Individuals with Pulmonary Nodules: General Approach 2. Assess the patient for risk factors for progressive thrombosis and risk of anticoagulation. Favors Anticoagulation Active cancer (particularly if metastatic or on chemotherapy) No reversible VTE risks (e.g. recent surgery) Marked symptoms without another cause Patient prefers anticoagulation Hospitalized or immobilized Favors No Anticoagulation High bleeding risk Patient prefers to avoid anticoagulation
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! What additional testing and follow up is recommended if the decision is to not anticoagulate SSPE? Additional testing recommended Bilateral US to exclude proximal DVT of the legs Exclude DVT in other high risk locations (e.g. upper extremities if a central line is present) Additional follow up Assure patient literacy surrounding signs and symptoms of progressive thrombosis Perform one or more follow up US of the legs to detect (and then treat) evolving proximal DVT
Whether to Anticoagulate Subsegmental Pulmonary Embolism NEW TOPIC! SUMMARY With a weak recommendation based on low quality evidence (Grade 2C), clinical surveillance is suggested over anticoagulation in patients with isolated subsegmental PE If clinical surveillance is chosen, it should be assured that no proximal DVT in the legs exists, and that the patient is at a low risk for recurrent VTE Upon clinical surveillance perform serial ultrasound of the legs to detect evolving DVT (e.g. repeating ultrasound weekly x 2 weeks)
Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy New TOPIC! AT10 Guideline Statement: In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban or edoxaban (and are believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C). Kearon C. CHEST 2016; 149(2):315-352
Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy New TOPIC! Risk factors for recurrent VTE while on anticoagulant therapy can be divided into two broad categories: (1) Treatment factors (2) Patient intrinsic risk of recurrence
Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy New TOPIC! TREATMENT FACTORS Important initial considerations when assessing for recurrent VTE on anticoagulant therapy (1) Was the patient adherent (2) Was warfarin sub therapeutic (3) Was anticoagulant therapy prescribed correctly (4) Was the patient taking a NOAC and a drug that reduced anticoagulant effect (5) Had anticoagulant dose been reduced (drugs other than warfarin)
Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy New TOPIC! INTRINSIC PATIENT RISK FACTORS FOR RECURRENCE Important considerations when assessing for recurrent VTE on anticoagulant therapy (1) Active cancer (occult disease should always be considered) (2) Antiphospholipid Syndrome i. Associated with recurrence ii. LA can interfere with the INR (spurious results) (3) Concomitant use of medications that increase risk of thrombosis
Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy New TOPIC! SUMMARY If a patient is on warfarin, then it is recommended to switch to treatment dose LMWH If a patient is on LMWH, then it is recommended to increase the dose by about 25% If anticoagulant intensity cannot be increased because of risk of bleeding, an IVC can be inserted to prevent PE This is a least favorable option of last resort
Aspirin for extended treatment VTE?
Aspirin for the secondary prevention of VTE AT10 Guideline Statement: In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B) Kearon C. CHEST 2016; 149(2):315-352
Aspirin for the secondary prevention of VTE Studies: 2 Participants: 1,224 Quality Evidence (GRADE) Hazard Ratio Difference Per 1,000 VTE Major Bleeding Mortality
Aspirin for the secondary prevention of VTE Anticoagulants reduce VTE >90% DOACS suggested if unprovoked & low risk bleeding Bleeding may be similar with ASA & DOACs SUMMARY Unprovoked proximal DVT or PE and stop AC & no contraindication then aspirin over no aspirin (Grade 2B)
Bridge therapy www.bridge1980.com; www.istockphoto.com; en.wikipedia.org
About 2.5M Americans require long term anticoagulation About 10% require interruption annually Anderson M Clev. Clin J Med, 2014, 8; 629;
Warfarin interruption for procedures Bridging Bridge Trial: Atrial Fibrillation RDBPCT 1884 pts. with AF Dalteparin or Placebo From 3 days before until AM before the procedure and then for 5 10 days after Demographics: mean age 72; 97.2% with CHADS 4 Time to first post procedure dose: 53h (H) 21h (L) Mean # Post Procedure doses: 16 Douketis JD etal. NEJM online 22 June 2014
Warfarin interruption for procedures Bridging Bridge Trial Results The incidence of arterial TE 0.4% in the no bridging group and 0.3% in the bridging group (95% CI 0.6 0.8; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the nobridging group and 3.2% in the bridging group RR 0.41 (95% CI 0.20 0.78; p= 0.005 for superiority). Conclusion: Forgoing bridging in AF patients was noninferior to bridging for stroke and decreased the risk of major bleeding. Douketis JD etal. NEJM online 22 June 2014
Warfarin interruption for procedures Bridging Warehouse Study: VTE Retrospective cohort study at Kaiser Colorado 1187 pts. on indefinite anticoagulation for VTE Demographics: mean age 66; 46% M 56% DVT 44% PE 79% low risk for recurrence at time of interruption 98.7% with VTE 3 mo. prior Procedures: GI Endo (37%) ortho (14%) spine (10%) abd sx (9%) Outcome: 30 d clinically relevant bleeding, recurrent VTE, and all cause mortality. Clark NP etal. JAMA Intern Med. Online May 26, 2015.
SW5 Warfarin interruption for procedures Bridging Warehouse Study Results There was no significant difference in the rate of recurrent VTE between groups (0 vs 3; P =.56). 30d bleeding in the bridge therapy and non bridge groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95%CI 3.9 75.1). Conclusion: Bridge therapy was associated with an increased risk of bleeding during warfarin interruption among VTE patients and is likely unnecessary for most. Clark NP etal. JAMA Intern Med. Online May 26, 2015.
Slide 51 SW5 Scott Woller, 8/23/2016
Generally, interrupt 4 5 half lives before HBR procedure OK to interrupt 2 3 half lives before LBR procedure Half life increases as renal function worsens Anderson M Clev. Clin J Med, 2014, 8; 629;
Pre procedural interruption of DOACs Adapted from Gladstone DJ Ann Intern Med. 2015;163:382 385.
Douketis J. Current Pharmaceutical Design, 2010, 16, 3436 3441
Why use warfarin decision support?
Anticoagulation management: icentra Why Clinical Decision Support in icentra? AT 9 Guideline For dosing decisions during maintenance VKA therapy, we suggest using validated decision support (e.g. computerized programs) rather than no decision support. Anticoagulation Forum When determining warfarin doses during VTE treatment we suggest using computer aided warfarin dosing programs over an ad hoc approach. Holbrook CHEST 2012; 141(2)(Suppl):e152S e184s; Witt D etal. J Thromb Thrombolysis (2016) 41:187 205
CDS outcomes within Intermountain
Pre Post warfarin management with CAC CDS Patient enrolled in CAC Time that the patient is taking warfarin INRs before CDS INRs after CDS n=2591 Woller, SC et al. Clin Appl Thromb Hemost. 2015 Apr;21(3):197 20
Results TTR=64% TTR=65.1% Woller, SC et al. Clin Appl Thromb Hemost. 2015 Apr;21(3):197 20
Results: Secondary Outcomes Major Complications Events, n BEFORE CDS Events/ 100 Pt. yrs. Events, n AFTERCDS Events/ 100 Pt. yrs. Percent Δ p value PE 59 0.85 23 0.27 68% <0.0001 VTE with hospitalization 96 1.38 47 0.56 59% <0.0001 Stroke 2 0.02 1 0.01 NA 0.7365 Major Bleed 77 0.91 94 1.30 +30% 0.0106 ED visit 3831 55 2876 34 38% <0.0001 Hospitalization 2943 42 2221 26 44% <0.0001 Woller, SC et al. Clin Appl Thromb Hemost. 2015 Apr;21(3):197 20
Comprehensive Anticoagulation CDS in icentra Initiation protocol Chronic protocol Bridging protocol DOAC Management* *Coming soon.
Anticoagulation CDS in icentra: workflow
Routine warfarin management in icentra Workflow for chronic anticoagulation management
Anticoagulation CDS in icentra: workflow
Anticoagulation CDS in icentra: workflow Clinician summary report
Anticoagulation CDS in icentra: workflow
Anticoagulation CDS in icentra: workflow
Anticoagulation CDS in icentra: workflow Patient Summary Report
Summary DOAC limitations & use in routine clinical care Special populations AT10 Updates: Venous Thromboembolism Anticoagulation procedural interruption ( bridging ) Warfarin DOACs Why & how to manage anticoagulation in icentra
QUESTIONS?