Update in Anticoagulation and Hypercoagulability In

DOAC in Clinical Practice

Jean M Connors MD

Medical Director, Anticoagulation Management and Stewardship Services Hematology Division Brigham and Women’s Hospital/Dana Farber Cancer Institute Associate Professor of Medicine, Harvard Medical School twitter @Connors_md

Agenda

• Direct Oral Anti Coagulant overview

• Approach to selecting a DOAC for your patient

• Niche populations – Cancer – Antiphospholipid syndrome – Renal failure Direct Oral Anticoagulants

Compared to warfarin direct oral anticoagulants offer: • Similar or improved efficacy and safety • “non-inferior” for efficacy in most situations • Major safety benefit is marked decrease in ICH • Pharmacologic advantages • Fixed dosing • Immediate onset of action • Ease of administration • no monitoring, no injections

Properties of Direct Oral Anticoagulants

Property Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban

Bioavailability 6 –7% 80% 66% 45% 34%

Tmax 1.5 hours 2 – 4 hours 1 – 3 hours 1 – 2 hours 3 – 4 hours

T½ 12 – 14 hours 9 – 13 hours 8 – 15 hours 9 – 11 hours 19 – 25 hours

Hepatic No Yes Yes Yes No Metabolism

Drug Interactions P-gp CYP3A4/P-gp CYP3A4/ P-gp P-gp P-gp

Protein Binding 35% 90% 87% 55% 60%

Renal Elimination 80% 35% 25% 50% 5-7% Why differences in major bleeding?

Kreutz JTH 2017

Pharmacokinetics and peak plasma concentrations: once vs twice a day dosing GI tract concentrations likely similar

FactorsFactors Affecting affecting DOAC therapeutic Efficacy and window Safety

• Concomitant drugs that change p-gp or CYP3A4 activity: affect plasma concentration – HIV anti-retrovirals, seizure meds, some antibiotics and antifungals, some chemo • Hepatic insufficiency • Weight—extremes • Renal insufficiency: check package insert • GI absorption factors • Age…….. Hepatic Insufficiency

• No or limited clinical trial data for use in patients with liver failure, so no dose recommendations available.

• Use in patients with mild impairment Childs A probably ok, risk benefit analysis.

• Do not use with moderate or severe impairment, Childs B or C,

• Coagulopathy due to hepatic synthetic function is the primary concern

Extremes of Weight

• Most trials enrolled patients between 60-100 kg. only 12% in VTE studies had BMI > 35 • One case report for dabigatran failure in 153 kg man, BMI 44.7, due to low drug concentration (NEJM 2013) • Current package inserts : Edoxaban: for VTE treatment reduce dose to 30 mg qd for patients < 60 kg Apixaban: reduce dose for weight < 60 kg and if age > 80 years or creatinine > 1.5 mg/dl • Use caution in patients <60 kg or >120 kg Age: dose modification

• Apixaban —age >80 considered a reason to dose reduce in the presence of 1 or more other risk factors, only DOAC with FDA approved dose adjustment for age.

• VTE studies: mean age 57 years • AF studies: mean age 71.5 years

• Age and renal insufficiency often concomitantly increased. Traditional methods of assessing CrCl may not apply to patients > 75 yrs+, however renal function not the only factor associated with increased bleeding in the elderly .

Approach to DOACidarucizumab Selection Consider: • Indication for treatment • Duration of treatment • Age • Weight • Renal function • Hepatic function • History and location of bleeding/bleeding risk • GI • Intracranial • Insurance coverage • Compliance My Approach for VTE

• Young patient limited duration – Rivaroxaban – Apixaban – Why: no need for parenteral agent • Old patient limited duration – Apixaban – Why: no need for parenteral agent • lowest renal clearance • less GI bleeding • lower peak intensity anticoagulation • Dose adjustment parameters for age and creatinine

My Approach for VTE

• Special situations – Must must must be able to reverse: dabigatran • Rivaroxaban and apixaban can use andexanet but shorter duration reversal effect – Crushed for feeding tube: apixaban, rivaroxaban – GI disorders prone to bleeding: apixaban – Cancer associated VTE: apixaban

• Extended duration * – Rivaroxaban – Apixaban * Usually unprovoked VTE My Approach for NVAF

• Young patient – Apixaban – Dabiagtran--superior for decreased ICH but 80% renal clearance – Rivaroxaban—once a day – No: edoxaban if CrCl > 95 ml/min *Cockcroft-Gault on MDCalc • Older patient – Based on renal function and GI bleed risk: – High GI bleed risk • Apixaban • Edoxaban – Low GI bleed risk • Any of them at appropriate renal dose

My Approach VTE Prophylaxis

• Post Orthopedic joint replacement – Rivaroxaban: once a day – Over age 80 and increased creatinine: Apixaban

• Extended Duration in the medically ill – Controversial, betrixaban and rivaroxaban approved – Patient risk factors should be fully assessed

• Off label VTE prophylaxis – rivaroxaban 10 mg once a day DOAC in antiphospholipid syndrome

“triple positive” APS – Anticardiolipin IgG or IgM – beta 2 glycoprotein1 IgG or IgM – Lupus anticoagulant or DRVVT • TRAPS trial : more recurrent events with rivaroxaban than warfarin • Arterial events MI and stroke even if 1 st event was venous

• Do not use DOAC in triple positive APS • Would not use in patients with arterial events even if only single or double positive • Would only use in low risk VTE if patient full aware of the data

DOAC for cancer associated VTE

RTC for treatment of cancer associated VTE • Edoxaban: Hokusai VTE cancer, 1046 patients • Rivaroxaban: Select-D, 402 patients • Apixaban: Caravaggio, 1160 patients • Compared to the LMWH dalteparin All had decreased VTE recurrence compared to dalteparin Differences in major bleeding • Edoxaban and rivaroxaban had increased major bleeding • Apixaban had the same rate of major bleeding • GI tract bleeding, especially with GI tract cancer and intact luminal primary was the reason for increased bleeds DOAC for cancer associated VTE

• Both risk of bleeding and recurrent VTE higher in patients with cancer • Patient selection important when treating cancer associated VTE • Non GI cancers: • assess bleeding risk, absorption, renal function • DOAC should be ok • GI tract cancers: • Asses location of tumor, metastases • Recent GI tract surgery? • N/V/D • Would use apixaban

DOAC in ESRD

• FDA approved for use in ESRD based on 1 dose given to 16 patients on dialysis • Data for long-term use is mainly retrospective and meta-analyses • RENAL–AF an RCT of warfarin vs apixaban stopped early due to loss of funding, presented at AHA Nov 2019. • 82 patients apixaban, 24 on 2.5 bid ; 72 warfarin, TTR 44% • Primary outcome CRNMB: 31.5% apixaban vs 25.5% warfarin • ICH: 1.2% apixaban vs 1.4% warfarin • GI bleeding 2.4% vs 8.3% • Major bleeding 8.5% vs 9.7% • Ischemic stroke 2.4% vs 2.8% • Cardiovascular death: 11% vs 5.6% • No statistically significant difference • More info on dose selection needed Apixaban pharmacokinetics at steady state in hemodialysis patients

non ESRD 5mg bid

Cmax 217 (45-658)

Cmin 111.3 (22-515 )

5 patients, day 15-22: 5 mg bid apixaban Almost 2 x higher Cmax and Cmin in ESRD

Mavrakanas J Am Soc Nephrol. 2017

DOAC Antidotes

• Specific antidotes are approved

• Randomized controlled trials have not been performed

• Reversal of anticoagulant effect has been the primary endpoint for all

• Andexanet also had co-primary endpoint of determination of hemostatic effect

• No comparison of final outcomes Approach to DOAC Selection

– Do not use at all in the following populations: – Mechanical heart valves*, other cardiac hardware – Pregnant patients

Would use with caution in: – Significant drug interactions – Difficult patients with recurrent events on standard therapy – Extreme obesity for early acute VTE treatment – Impaired GI absorption – Lack of compliance

*absolute contraindication: RE-ALIGN trial, LVAD data

Summary: how to decide

• Younger patients do well with either DOAC or VKA with no real difference in bleeding rates. Older patients appear to do better with DOAC for ICH but not GI bleed – Assess factors such as compliance, testing, bleeding risk—ie inflammatory bowel disease, AVMs, elderly and GI bleed risk

• Dose adjustment for renal insufficiency varies by drug – Would use cautiously in patients with fluctuating renal function or close to the edge of recommended CrCl – Would use very cautiously in dialysis patients until more data available • Do not use in patients waiting for cadaveric renal transplant Summary: how to decide

• Patients with acute VTE should be treated with DOAC unless contra-indications

• Patients with AF should be treated with a DOAC unless mitigating factors

• Co-pay programs available from all companies although donut hole and other insurance issues may make DOAC cost prohibitive—be aware that this is also true for LMWH

Adherence

Retrospective case cohort study:12,129 patients with new start AC, 2009-2013 Kachroo Am J Manag Care 2016 Coagulopathy in the era of COVID-19

Jean M Connors MD

Conflicts of Interest

Scientific Ad Boards and Consulting: Abbott Bristol-Myers Squibb Portola Takeda

Research funding to the Institution CSL Behring

Jean M Connors MD Agenda

What is COVID-19 coagulopathy

What contributes to it

What should we do about it?

COVID-19 associated Coagulopathy

Data from Wuhan demonstrated coagulation test abnormalities – Elevated D-dimer – Elevated fibrinogen – Mild prolongation of PT , rarely PTT – Thrombocytopenia uncommon – DIC much less frequent • Occurs in patients with pronged hospitalization, sepsis, superinfection, other ICU associated causes

– Marked increase in D-dimer associated with severe disease and mortality – Also drop in platelets and increase in PT correlate with severity 4/22/20 28 “Coagulopathy”

Not “coagulopathy” as a hematologist interprets it: no bleeding Il-6 levels correlate with fibrinogen levels ESR and CRP elevated Thromboinflammation : driving coagulation – Interaction between inflammatory pathways and coagulation – Many pathways • Increased levels of fibrinogen, FVIII, vWF • Intrinsic coagulation pathway activated • Platelets activated • Endothelial cell dysfunction • Stasis in small vessels COVID-19 is a hypercoagulable state

D-dimer

• D-dimer assay not standardized • Produced when plasmin cleaves cross-linked fibrin

• Can be elevated in many other situations besides COVID-19 – Lacks specificity • Inflammation can result in levels >1000 ng/ml 1647 ER patients tested for D-dimer Lippi, EJIM 2013 Coronavirus

• Biomarkers • 191 patients – 54 non-survivors – All met sepsis definition – Half had 2nd infection – OR for death with elevated D-dimer at admission 18 (2-128, p0.003)* – Mortality also associated w/ age and high SOFA

Tang 1

21 non-survivors 162 survivors PROCOAGULANT PATTERN WITH COVID-19 ARDS

Ranucci: JTH 2020: Apr17 ePub

Thromboinflammation

Shaun P. Jackson et al. Blood 2019;133:906-918

Basement Type-1 pneumocyte membrane Fibrin Type-2 pneumocyte SARS-CoV-2 TLAIL

Vascular Resident alveolar Lymphocyte endothelial cell macrophage

Neutrophil

MCP-10 IP-10 MIP-1 Cell death Type-H

Reactive oxygen NETs species, Inflammatory mediators Type L : vessel damage Platelet Interstitial minimal alveolar damage edema Type-L MAC Fibrin degradation products Type H : both vessel, alveolar damage Inflammatory thrombus Iba , CCM 2020

Antithrombotic function of endothelial cells.

Shaun P. Jackson et al. Blood 2019;133:906-918

LUNG

Mononuclear and PMN RENAL SMALL BOWEL microvascular infiltration

Capsase3 staining: apoptosis in endothelial and mononuclear cells A/B: renal: viral inclusion bodies/C: small bowel/capsase 3 staining/ D: lung Varga, LANCET 2020

COVID-19: endothelialitis and autopsy findings

• Microthrombi in alveolar capillaries • Interstitial and perivascular lymphocytic infiltrates • Multifocal endothelialitis Ackermann NEJM May 21 COVID-19: endothelialitis and autopsy findings

Ackermann NEJM May 21

COVID-19: thrombosis data Worldwide cumulative incidence VTE in ICU patients on prophylaxis

– Netherlands (Klok): symptomatic VTE 27% at 14 days • nadroparin 2850 IU • Include PE, DVT, MI, ischemic stroke, arterial embolism = 31 %

– Netherlands (Middeldorp): symptomatic 7d = 11%, 14 d = 23%; HR 2.9 • nadroparin 2850 IU daily

– France (Helms): ARDS 11.7% in covid-19+ vs 2.1% non-covid-19+; OR 6.2 • At least chemoprophylaxis 4000 IU enoxaparin

– France (Poissy): PE in ICU patients with COVID-19 vs other ICU cohorts • 20.6% COVID-19+ (107 pts) • 6.1% time matched Feb-Mar 2019 (196 pts) • 7.5% Influenza Jan 2019– (40 pts) – BWH: ICU 14 day cumulative incidence 9.3%, 4x higher than ward BWH Anticoagulation Strategy

COVID-19 Coagulation Standard dose Escalated 1 Therapeutic positive tests VTE prophylaxis dose VTE dose prophylaxis anticoagulation Outpatient Consider 2 Inpatient X Ward X X ICU X X

Confirmed VTE X X Presumed PE 3 X X

ARDS X X

Connors and Levy Blood 2020

Revised BWH ICU VTE Prophylaxis Dosing – COVID

VTE Dosing Weight CrCl ≥ 30mL/min CrCl < 30mL/min Adjustment Enoxaparin 40mg UFH 7,500 units Standard BID Q8H Obese (> 120kg or Enoxaparin UFH 10,000 units BMI > 35) 0.5mg/kg BID Q8H (max dose 100mg BID) Low Body Weight Enoxaparin 30mg UFH 7,500 units (< 60kg) BID Q8H Do not use therapeutic dose anticoagulation unless clinically indicated COVID-19: anticoagulation approach

Outpatients – Consider for patients with concomitant high risk factors Inpatients – Ward: standard dose, adjusted for extremes of weight and renal function – ICU: intermediate intensity, adjusted for weight and renal fcn – Discharged from ICU; intermediate intensity When should therapeutic dose heparin be used? – Suspected PE : sudden decompensation in oxygenation, tachycardia, RV strain, new LE DVT – Not routinely in ICU patients unless in a clinical trial Risk adapted strategies—we are not using – D-dimer levels, ESR/CRP, ferritin, IL-6, fibrinogen Discharged home – Extended duration prophylactic dose for 4 weeks if no thrombosis – Confirmed VTE: therapeutic dose for at least 3 months

COVID-19: summary multiple hits result in thrombotic pathology – Marked elevation in procoagulant proteins – Disrupted/destroyed antithrombotic protection by vascular endothelial cells – Stasis in small capillaries due to inflammation and debris ICU patients at highest risk – More severe inflammation and stasis – Macrovascular events • Venous higher incidence than arterial but both occur – Microvascular thrombosis and ARDS Randomized controlled clinical trial data are needed to determine appropriate dose of heparin in patients without documented thrombosis COVID-19: summary

Prevalence of VTE is higher in patients with COVID-19 Dose for VTE prophylaxis in COVID-19+ not known – Dose for post-op or medically ill appears insufficient for critically ill patients – “intermediate” dose not validated – Risk adapted approaches even less so – Many studies started, effect on VTE and mortality TBD When should therapeutic dose heparin be used? – Only in trials if no clinical indication Additional strategies? – Need to control the virus to recover – Microvascular plus venous and arterial thrombosis occur – Thrombotic microangiopathy due to endothelialopathy plays a role

COVID-19: summary

Additional strategies: Need to control the virus to recover • Antivirals • Anti-inflammatory/anti-cytokine Macrovascular venous and arterial thrombosis occur • Is LMWH prophylaxis sufficient? • Full dose anticoagulation? • tPA • Defibrotide and others “Thrombotic microangiopathy” due to vascular disturbance • Razuprotafib (protein tyrosine phosphatase ß (HPTPß) inhibitor) • Eculizumab • Plasmapheresis/caplacizumab