Hemostasis and Thrombosis Update for Primary Care Providers. Primary Care Medicine: Principles and Practice. Topic Outline

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(1)QPDQRDQT. Hemostasis and Thrombosis Update for Primary Care Providers Primary Care Medicine: Principles and Practice )-5? 4$2<. /*-RR<RPQT. Topic Outline Non-Vitamin K antagonist Oral Anti-Coagulants – NOACs • Background on these agents • Use of Specific Agents in Venous Thromboembolic Disorders • Drug Interactions • Reversal • Laboratory Monitoring • My patient needs a procedure. D-dimers and ‘elderly’ patients Choosing Wisely – The American Society of Hematology • The case against thrombophilia testing. Q.

(2) QPDQRDQT. Lets Just Agree on a Name* New Oral AntiCoagulants – NOACs Novel Oral AntiCoagulants – NOACs Target-Specific Oral Anti-Coagulants – TSOACs Direct Oral AntiCoagulants – DOACs Oral Direct Inhibitors – ODIs Non-monitored Oral AntiCoagulants – NOACS Non-warfarin Oral AntiCoagulants – NOACs Non-vitamin K antagonist Oral O AntiCoagulants – NOACs Non-vitamin *Husted et al. Thromb Haemost 2014;111:781-82. NOACs – A Few Take Home Points Up Front All have a black box warning with two key points: Premature discontinuation increases risk of thrombotic events These findings are from the Atrial Fibrillation trials Therefore: Parenteral bridging if NOAC to Warfarin Spinal/Epidural Hematoma Need protocols for stopping pre/starting post procedure. Decline in renal function leads to increased bleeding risk Think elderly, NSAIDs, Nausea/vomiting/dehydration, etc.. Be sure proceduralist is aware your patient is taking the medication Do not use with mechanical heart valves. R.

(3) QPDQRDQT. Warfarin: 60+ Years Old & Going Strong 1920’s: cattle in northern US plains started dying of internal bleeding Sweet Clover Disease – manifest in 15 days; dead in 30-50days Wisconsin Alumni Research Foundation (WARF) funded the research Dicoumarol patented in 1941 by biochemist Karl Paul Link Of 150 derivatives, #42 was more fast acting and potent, and had good water solubility and oral bioavailability. Patent in 1945. WARFarin (Coumadin) PE study Barritt and Jordan (1960): heparin & warfarin 16 W/ Rx: none died of PE and 0 non-fatal recurrences 19 W/O Rx: 5 died of PE and 5 non-fatal recurrences.. Wardrop and Keeling, BJH 2008;141:757-63. NOACs – 4 Years Young! g. (PRADAXA). 2014. 2014. 2011. 2013. 2013. 2014. 2014. 2010 (XARELTO). 2012 (ELIQUIS). 2012. 2009-2014: Yr FDA Approved. 2014. 30 Phase III studies Involving >170,000 patients For 6 different indications AND – 3 NOACs FDA approved. Table & numbers from: Schulman, Thromb and Haemost (2014)111:575-82; and thanks to Ken Bauer, MD. S.

(4) QPDQRDQT. What Do Theyy Look Like? Dabigatran – PRADAXA QUP(". QQP("L. RP(". QU(". U(". R?U(". WU(". Rivaroxaban - XARELTO QP(". Apixaban - ELIQUIS. L$"/-)QQP(")*/4$''$)/#. Coagulation Cascade in Patients Tissue Factor. XI. Tissue Factor. Tissue Factor. TF TF TF TF. XIa. TF VIIa. . . IX X. Ca+++/Pl /Pl. . TF/VIIa TF/VIIa / Rivaroxaban Apixaban. +++. X = Warfarin. Ca /Pl /Pl. . II Fibrinogen. Dabigatran. Fibrin . X-linked Fibrin. Tissue Factor. Tissue Factor. Tissue Factor. T.

(5) QPDQRDQT. NOACs – some important characteristics. 66% %. Table from: Schulman, Thromb and Haemost (2014) 111:575-82. VTE Prophylaxis – Orthopedic Setting DOSING. Rivaroxaban (XARELTO). Hip Replacement. Knee Replacement. 10 mg qD x 35D1. 10 mg qD x 12D1. Start 6-10 hrs post-op* Apixaban (ELIQUIS). 2.5 mg BID x 35D1. 2.5 mg BID x 12D2. Start 12-24 hrs post-op* *Provided that adequate hemostasis has been achieved. RESULTS: Reduction in VTE; No increased bleeding 1Compared. to 40 mg subQ qDay or 230mg subQ q12 enoxaparin started 12 hours before surgery. U.

(6) QPDQRDQT. DVT and PT (VTE) Treatment Phases Initiation of Treatment: • Unfractionated heparin IV (aPTT monitoring) or LMWH for at least 5 days, serves as bridge. • VKA starts day 1 and need INR>2 for 2 days. Long-term Primary Treatment • VKA for 3-6 months with INR 2-3. Extended or Prevention Treatment • Option for first unprovoked or recurrent VTE • Indefinite duration. VTE Treatment - Primary DOSING* . Traditional. $/($)

(7) )/"*)$./ Day 1 ~Day Day 7 7-10**. Dabigatran 2,539 pts w/ DVT + PE. Rivaroxaban 3,449 pts w/ DVT 4,833 pts w/ PE + DVT. Apixaban. Day 1 ~Day 7-10. “BRIDGING”. 3-6 months. $"/-)QUP(" “SWITCHING”. 6 months. $4-*6)QU(" S5&.M/#)RP(",7 3, 6, 12 months. +$6)QP(" Q5&M/#)U(" . 5,395 pts w/ DVT + PE. *All compared to ‘traditional’ approach; not tested in CrCl <30. 3, 6, 12 months. ** Until INR >2 for 2 days. V.

(8) QPDQRDQT. -/()/E3/*(. Initial Treatment Phase *. CRNMB=clinically relevant non-major bleeding; CI=confidence interval. *Recurrent symptomatic VTE or related death; *P value for non inferiority for Primary efficacy outcome is <0.001 for all agents. Table from: Schulman, Thromb and Haemost (2014) 111:575-82. -/()/E3/*(. Extended (Prevent Recurrence) Treatment Phase. CRNMB=clinically relevant non-major bleeding; CI=confidence interval; P=placebo. Table from: Schulman, Thromb and Haemost (2014) 111:575-82. W.

(9) QPDQRDQT. Drug Interactions • Permeability Glycoprotein (P-gp): Efflux transporter Locations: GI Tract (Enterocytes), Liver, Kidneys Stimulation: Inhibition:. Decreases Drug Levels Increases Drug Levels. • Cytochrome P450 System: Involved in Drug Metabolism CYP3A4:. Most prevalent of all CYP in liver Oxidizes a wide range of chemically diverse drugs. Stimulation: Inhibition:. Decreases Drug Levels Increases Drug Levels. Dabigatran (PRADAXA) Rivaroxaban (XARELTO) Apixaban (ELIQUIS). P-gp P-gp & CYP3A4 P-gp & CYP3A4. Drugs That Affect P-glycoprotein and/or CYP3A4. , cyclosporine, tacrolimus. Copyright © by SAGE Publications. Hellwig &Gulseth Annals of Pharmacotherapy 2013;47:1478-87. X.

(10) QPDQRDQT. Dabigitran (PRADAXA): Renal Function* Renal Function. CrCl (ml/min). Increase in AUC. Increase in Cmax. T1/2 (hr). Normal. >80. 1X. 1X. 13. Mild. 50-80. 1.5X. 1.1X. 15. Moderate. 30-50. 3.2X. 1.7X. 18. Severe. 15-30. 6.3X. 2.1X. 27. Renal Clearance for NOACs: Dabigatran: ~80% Rivaroxaban: ~66% Apixaban: ~25% *Table from Package Insert. The Approach One Person Has Taken…. Cushman M. N Engl J Med 2013;369:865-866.. Y.

(11) QPDQRDQT. NOAC Reversal – Stay Tuned Antidotes or Reversal Agents = NONE BUT, IN DEVELOPMENT… Dabigatran: Antibody Xa inhibitors: Decoy, crippled Factor Xa • catalytically inactive as a protease • lacks the membrane binding γ-carboxylase domain. RETAINS: • Ability to bind Xa inhibitors • Ability to bind & reverse Antithrombin-dependent anticoagulation by enoxaparin or fondaparinux • Reverses lab tests and bleeding in animals. NOAC Bleeding…NOW! Nothing proven, but options to consider... • Charcoal gavage if within ~2 hours of ingestion • Dialysis for Dabigatran, which is only ~1/3 protein bound Rivaroxaban and Apixaban >90% protein bound • rF7a • Prothrombinase Complex Concentrates 4-factor now available in US, but no demonstrated benefit • Activated Prothrombinase Complex Concentrates: FEIBA – but no demonstrated benefit. QP.

(12) QPDQRDQT. NOACs & Laboratory Testing No Published Data Correlating Drug Level and Efficacy/Hemorrhage aPTT and PT: too insensitive, too sensitive, no clear dose response Direct Thrombin Inhibitor – Dabigatran: aPTT more sensitive than PT -But, not standardized and prolongation not predictable -And, normal aPTT does nott rule out ‘on therapy’ drug level Thrombin Time is exquisitely sensitive If normal, then essentially no clinically li significant drug in system Xa Inhibitors - Rivaroxaban & Apixaban: Need chromogenic Factor Xa activity assay standardized to the Rx PT iis more sensitive iti than th is i the th aPTT aP PTT -But a normal PT does not rule out ‘on therapy’ drug level No effect on Thrombin Tine. NOACs: Effects on ‘other’ Coagulation Laboratory Testing DTI and Xa inhibitors can: Decrease individual factor levels (activity assays) Give false positive lupus anticoagulant assays Falsely increase in Protein C and Proteins S activity assays (clot based) Impair correction in 1:1 plasma mixing assays. QQ.

(13) QPDQRDQT. NOACs and VTE – some thoughts Patients with thrombophilia: No data but no a priori reason that they will not work Could they have a role for AT deficiency or Protein C deficiency? Heparin-induced thrombocytopenia: No data – will be interesting to see how this evolves I would not use at this time for: Cancer-associated or Pregnancy-associated VTE: Massive PE: hemodynamic instability/considering thrombolysis Massive DVT with phlegmasia cerulea dolens “Extremes’ of weight: <110 or >250 pounds If happy and stable on coumadin – do not switch Be very aware of renal function and ‘other’ medications. My Patient Needs a Procedure Guidelines for neuroaxial* procedures:. *lumbar puncture, subarachnoid block (spinal), intrathecal catheter, epidural catheter, epidural steroid injection, & others. The are Guidelines to help orient your thinking. Professional clinical judgment is required for proper care in all clinical encounters. Thanks to M. Fang, MD, S. Kayser, Pharm D, and R. Naidu, MD (UCSF). QR.

(14) QPDQRDQT. My Patient Needs a Procedure. *lumbar puncture, subarachnoid block (spinal), intrathecal catheter, epidural catheter, epidural steroid injection, & others. The are Guidelines to help orient your thinking. Professional clinical judgment is required for proper care in all clinical encounters. Thanks to M. Fang, MD, S. Kayser, Pharm D, and R. Naidu, MD (UCSF). D-Dimers and PE Diagnosis in Older Patients D-Dimer <500 ug/L & low/intermediate or unlikely clinical probability: Rules out 60% of PEs if <40 yr old; but only <5% if >80 yr old1. Retrospective multicenter cohort study devised a new age-based cut off value to rule out PE:2 Patient age x 10 ug/L if >50 years of age The new Equation was prospectively evaluated in 19 hospitals in Belgium, France, Switzerland, and The Netherlands3. 1Righini. et al J Thromb Haemost 2007;5:1869-77.; 2Douma RA, et al BJM 2010;340:1-7; 3Righini et al JAMA 2014;311:1117-24. QS.

(15) QPDQRDQT. D-Dimers and PE Diagnosis* -*.+04<*).304+0)/.+-.)0)"/* 3/*)./*-5*-.)$)"#./$)*- ....'$)$''77$(+'$!<-4$.)4.*-H'*5<$)/-($/<#$"#I *-RE'4'''..*-H3)'$&'7<'$&'7I SSRT+0)/.)-*''-*( )RPQPFRPQS? -$/-$>*/@#$"#'$&'7A*-@)*/'$&'7A]RXYX+0)/.HXW\I QQUT#E$(-'*5"E%3./3/E* XQW#E$(-'*5UPP SSW5$/#E$(-/5)UPP)"E%3./3/E* > QQ?V\.*'3/$)-.*-TQ?R\-'04$)-.$)B)"04CE$(-/./. S > XQW]^UPP> Q)*)/'>P?Q\HYU\ >P?PEP?W\I SSW]UPPF"E%3./>Q)*)/'=P?S\HYU\ P?QFQ?W\I

(16) WVV+0)/._WU7-*'>VWS)*/#$"#*-'$&'7> "%3./$)-..-3'*3/7*4-T*'HV?T\/*SP\I *Righini et al JAMA 2014;311:1117-24. D-Dimers and PE Diagnosis Simplified, revised Geneva Score. 2-Level Wells Score. *Righini et al JAMA 2014;311:1117-24. QT.

(17) QPDQRDQT. Choosing Wisely® A medical stewardship and quality improvement campaign spearheaded by the American Board of Internal Medicine Foundation Challenges medical societies to identify 5 tests, procedures or treatments offered to patients despite lack of evidence demonstrating benefit The Institute of Medicine estimates that nearly 1 in 3 dollars spent in healthcare is wasted and that diagnostic testing is a significant contributor 1 of the 5 American Society of Hematology (ASH) recommendations (#2) relates to hemostasis and thrombosis Recommendation #2: Do not test for thrombophilia in adult patients with venous thromboembolism occurring in the h setting of major transient risk factors, such as surgery, trauma, or prolonged immobility. Choosing Wisely – The data* B*)*/* -/#-*(*+#$'$/.0)"/*+0)/.5#*-*)0)3$)")0*"3'0*) /-/()/<*-/*/#*.5#*#4#B+-*4*&C*-+3'(*)-7(*'$.(H/#/$.< +0)/.5#*$)/#+.//#-(*)/#.#4#/-).$)/(%*-'$)$'-$.&/*- *-4)*3./#-*(*(*'$$..IG*-6(+'<.3-"-7</-3(<+-*'*)" $((*$'$/7H*)!)/*<3)'/*5'&3)$<*-'$&'7/*.+).3./)0' +-*+*-0*)*/#7$)*-$)#$-I<+-"))7<*-+3-+-$3(G*-+0)/.5#* -#4$)"#*-(*)'/#-+7H*-'*)/-+0*)*-#*-(*)-+'()//#-+7I?C J

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(24) K *Chong et al BMJ 2012;344. “Management of venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE guidance”. B#-*(*+#$'$.-)$)"*#*.+$/'$8+0)/./*$)07+0)/./-$.&* #*.+$/'E,3$-4)*3./#-*(*.$.$.)*/$)$/HQI?C *Baglin et al BJH 2010 (149) 209-20. “Clinical guidelines for testing for heritable thrombophilia”. QU.

(25) QPDQRDQT. #)&7*3*-7*3-2)0*): 3.0*).;. UCSF Non-malignant Hematology Clinic For Referrals: 415-353-2051 (phone line) 415-353-7765 (fax line) Andrew D. Leavitt 415-514-3432 leavitta@labmed2.ucsf.edu. QV.

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