Hematologic Problems Including Bleeding, Clotting, Venous Thromboembolic Disease and

Newer Anticoagulant Drugs

Thomas W. Wakefield MDStanley Professor

Section of Vascular SurgeryDirector Samuel and Jean Frankel Cardiovascular Center

University of Michigan

Andrea T. Obi MDAssistant Professor, Vascular Surgery

University of Michiganeasta@med.umich.edu

Disclosures

None

Arterial versus Venous thrombosisCommon “truths”

Arterial thrombi are white

Venous thrombi are red

“venous and arterial thrombosis are two different diseases with regards to pathophysiology, epidemiology and treatment strategies”

Harrison’s Principles of Internal Medicine 17th ed. New York: McGraw-Hill; 2008.

STEMI thrombi~69% are red

current truth:

arterial thrombi have rbcs

venous thrombi have platelets

composition differs based on timing and etiology (and shear)

Quadros AS, et al. American Heart J 2012:164:553-560

flow chambers studies:platelet recruitment as shear

Jackson SP. Nature Med 2011; 17:1423-1436

arterial venous

Shear

arterial venouslocation anatomic or physiologic

pre-disposed areas>90% lower extremities

clinical significance tissue tolerance to hypoxia

local/systemicconsequences of thrombus/emboli

local environment high shear (~30ml/s) low shear (1-4ml/s)mechanism erosion, ulceration,

rupture of plaquestasis, vw injury, hypercoaguability

endothelial injury/activation

platelet-EC interactionTF releasepr

imar

y he

mos

tasi

s

Arterial versus Venous thrombosis

Total US 2002 VTE EventsIncident & Recurrent, Fatal & Non-Fatal

Event Community-acquired Hospital-acquired Total

Non-fatal VTE

DVT

PE

193,598

108,240

85,358

419,825

268,125

151,700

613,423

376,365

237,058

Fatal VTE

DVT

PE

106,551

649

105,902

189,819

1609

188,210

296,370

2258

294,112

Grand Total 300,149 609,644 909,793

*Events occurring with 90 days after hospitalization were categorized as hospital-acquired.

Heit JA, Cohen AT, Anderson FA Jr. Blood 2005;106(11):abstract #910, p. 267a

VTE represents a commonly encountered post-operativecomplication for the vascular surgeon.

VTE rate is 9.4%–13.2% following lower extremity amputationBandeira FC et al, Intl Angiol 2008; 27:489-493; Struijk-Mulder MC et al, JTH 2010; 8:2680-268

VTE rate is 2.4% in patients undergoing open aortic surgery; increases with each risk factor (to a maximum of 8% with ≥4 risk factors): operative time ≥ 5 hours, chronic

steroid use, preoperative dyspnea, body mass index (BMI) ≥ 30, post-operative pneumonia, post-operative mechanical ventilation >48 hours or return to operating room within 30 days

Scarborough JE et al, J Am Coll Surg 2012; 214:620-626

Among all types of outpatient surgery, superficial venous procedures carry the highest risk for VTE (adjusted ORs 13.2 and 15.6)

Pannucci CJ et al, Ann Surg 2012; 255:1093-1099

Delay in chemoprophylaxis following open lower bypass or aortic surgery increases the risk of VTE (OR 2.38)

Sutzko D et al, J Vasc Surg 2018; 67:262-271

United States health costs for VTE, total hospital acquired VTE, and total preventable

VTE (2011 dollars)

Total VTE $32.1-69.3 BillionHospital Acquired $23.7-51.5 BillionPreventable $11.9-39.3 Billion

Mahan CE et al, Thromb Haemost 2012; 108:291-302

Economics

Virchow’s Triad (1856)

Circulatory stasis

Endothelial injuryHypercoagulability

Moll and Mackman ATVB 2008; 28:367-369

mp

mp

mp

mp

mp

mpP-selectin

E-Selectin and P-Selectin Involvement in Thrombosis and Inflammation

Activation

MigrationAdhesion

Endothelium

Thrombosis

PMN

Monocyte

ActivatedPlatelets

TF

Tissue FactorRich Microparticles

TFTF

PSGL-1

PSGL-1

ESL-1

Thrombus Amplification

mp

E-selectin

mpmp

mp mp mp mpmp

mp

E-Selectin and P-Selectin Involvement in Thrombosis and Inflammation

MigrationAdhesion

Endothelium

TF

Nuclear Material (NETs)

TFTF

nm

Fibrin Strands

nmnm

nm

MAC-1 (αMβ2)

Risk Factors for VTEAge (1.69 HR increase) Puurunen MK et al, Thromb Res 2016

Immobilization (2-3 fold increase) Sigal B et al, Ann Surg 1974; Heit Jet al Arch Intern Med 2000Fujii Y et al, Thromb Res 1992

Travel (150 fold at 5000km) Lapostolle F et al, NEJM 2001

History of VTE (1 in every 11 to 50) Coon WW et al. Circ 1973; Simioni P et al, NEJM 1997

Obesity (HR 1.88 with BMI > 30) Puurunen MK et al, Thromb Res 2016

Malignancy (4 fold compared to without) Heit J et al, Arch Intern Med 2000

Surgery (half after discharge) Kakkar V et al, Am J Surg 1970; Macklon and Greer, Scottish Med J 1996

Trauma (13 fold increase) Heit et al, Arch Intern Med 1999

Inherited Thrombophilia (depends on type) Pregnancy (5-10 fold increase) Heit J et al, Ann Intern Med 2005

Oral Contraceptives/Hormonal Tx (2.9 fold incrase) Saltzman and Hirsh, 1994

Central Venous Catheters (14 fold, 4 fold PICC) Winters JP et al, JTH 2015

IBD (3 fold increase) Nguyen GC et al, Gastroenterology 2014; Alatri A et al, Scan J Gastroenterology 2016

SLE (3-4 fold increase) Avina-Zubieta JA et al, Sem Arth Rheum 2015

SLE with LA (6 fold); with ACA (2 fold) Wahl DG et al, Lupus 1997

Schulman S, Best Pract Res Clin Hem 2012; 25:361-377

Most Common Symptoms and Signs of VTE – all nonspcific - along with differential diagnosis

DVT PEPain deep in calf or thigh Pleuritic painUnilateral swelling DyspneaIncreased temperature of leg SyncopeTenderness HemoptysisRedness Palpitations

Differential DiagnosisBaker’s cyst Respiratory tract infectionMuscle injury Myocardial infarctionCellulitis PericarditisSuperficial Thrombophlebitis Musculo-skeletal problemsPTS

NEJM 2003

A well’s score of ≤ 2 and negative D dimer effectively rules out DVT

…and reduces unnecessary duplex scans by about 40%

Duplex is the gold standard for diagnosis of DVT (Sen/Spec > 95%)

Anticoagulation is the mainstay of therapy for VTE

No anticoagulation Anticoagulation

Recurrent thrombosis

29-47% 4.7-7.1%

PE 26-67% 0.4-2.0%

Risk of major bleeding ~3%

Initial Treatment

Management of Acute Proximal Lower Extremity DVT

For assessment of severity, use Villalta score.** When phlegmasia (alba or cerulean dolens) orvenous gangrene is present (rare):•urgent vascular surgery consultation AND•Initiate anticoagulation

Grant PJ, Courey AJ, Hanigan S, et al. Guidelines for Clinical Care Inpatient, Special Topics in Venous Thromboembolism” [Internet]. Ann Arbor (MI): Michigan Medicine University of Michigan; 2019 Feb http://www.uofmhealth.org/provider/clinical-care-guidelines and at

https://www.ncbi.nlm.nih.gov/books/NBK544377/. PMID: 31339682

Guidelines emphasize risk factors and bleeding risk

Low to moderate bleeding risk

High bleeding risk

Acute provokedproximal DVT

3 months (1B) 3 months (1B)

Acute unprovoked proximal DVT

Extended therapy (2B)

3 months (1B)

Cancer associated DVT

Extended therapy (1B)

Extended therapy (2B)

Summary of ACCP 2016 guidelines

VTE RecurrenceHighest Risk within the first 6-12 months

1 year 5 yearsMajor Reversible Risk Factor 3% 10%Minor Reversible Risk Factor 5% 15%Unprovoked DVT 10% 30%

Independent Predictors of Recurrence:Male Gender; Increasing Age; Increasing BMI;

Neurologic Disease with Leg Paresis; Active Cancer; Idiopathic Etiologies; Lupus AC/APA; AT, Protein C or S

Deficiency; Elevated Plasma D-Dimer; Residual Venous ThrombosisHeit JA et al, Arch Intern Med 2000; 160:761-768

Baglin T et al, Lancet 2003; 362:523-526Ruth A, Kessler CM, Caprini JA. Pacific Vascular-V, 2006

Heit JA, ATVB 2008; 28:370-372

Becattini G and Agnelli G. Blood 135:305-316, 2020

Clinical Signs Indicative of Possible Thrombophilia

• Thrombosis at a young age (<40 yrs)• Unprovoked thrombosis• Recurrent thrombosis• Thrombosis at an unusual site

Mesentery, CNS venous sinus, portal vein• Family history of thrombosis, particularly

unprovoked, severe and in individuals <50 years of age

Table 5-6 Prevalence of Thrombophilia and Relative Risk Estimates for Thrombosis Antithrombin

deficiency Protein C deficiency

Protein S deficiency

Factor V Leiden Prothrombin 20210A

Prevalence in general population

0.02% 0.2% 0.03%-0.13% 3%-7% 0.7%-4%

Prevalence in consecutive VTE patients

1% 3% 2% 20% 5%

Relative risk for 1st VTE

5-10 4-6.5 1-10 3-5 2-3

Relative risk for recurrent VTE

1.9-2.6 1.4-1.8 1.0-1.4 1.4 1.4

Relative risk for arterial thrombosis

No association No consistent association

No consistent association

1.3 0.9

Adapted from Middeldorp S. Inherited thrombophilia: a double-edged sword. ASH Education Book. 2016; vol. 2016(1): 1-9. VTE, venous thromboembolism.

16x

0.02-0.2%

7.5x 5.4x

Moran J and Bauer KA, Blood 135:344-350, 2020

4x (11x Homo) 3x (6.7 Homo)

1.4x 0

Gestational Risk HomoFVL, HomoPT20210A, Het FVL + PT20210A, and severe ATIII: >2 to 3%

3.6x 2.9x 0

0.2-0.4% 0.03-0.5% 4-6% (Whites) 2% (Whites)

12-20% 6%

Connors JM. N Engl J Med 2017; 377:1177-1187

Summary of Recommendations Regarding Testing for Thrombophilia

Stevens SM et al, J Thromb Thrombolysis 2016; 41:154-164

Post thrombotic syndrome

Thrombus collagen

2 major components:1. Venous obstruction (can be treated by venous recanalization and

stenting)2. Fibrotic and thickened valves lead to reflux (no effective treatment)

Ambulation/Stockings

Rate and Severity of Postthrombotic Syndrome after Proximal DVT can be cut by 50% by the use of

Compression StockingsBrandjes DP et al, Lancet 1997; 349:759-762

Prandoni P et al, Ann Int Med 2004; 141:249-256

Walking with Good Compression does not Increase the Risk of PE, while significantly Decreasing the Incidence and

Severity of the Postthrombotic SyndromeSchellong SM et al, Thromb Haemost 1999; 82(Suppl 1):127-129

Aschwanden M et al, Thromb Haemost 2001; 85:42-46Partsch H et al, Sem Vasc Surg 2005; 18:148-152

Kahn SR et al, Lancet 2014; 383:880-888

In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent PTS (Grade 2B).

Remarks: This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms,a trial of graduated compression stockings is often justified.

ACCP guidelines 2016Compression Stockings

Immediate Application of Stockings

592 adult patients from 10 academic and nonacademic centersProximal DVT

No Compression or Acute Compression within 24 hours of Diagnosis with either multilayer bandaging (62%) or stockings (26%)

Presence of RVO and Recurrent VTEPTS defined as Villalta at least 5 at 24 months

RVO Compression vs. No Compression (46.3% vs. 66.7%, p = .005)PTS Less Prevalent in those without RVO (46% vs. 54%, p = .013)

Recurrent VTE – No Association

Amin EE, Bistervels IM, Meijer K, et al. Blood 132:2298-2304, 2018

Dabigatran Rivaroxaban Apixaban EdoxabanAF Dosing 150mg BID 20mg Daily 5mg BID 60mg Daily

AF Dosing (renally adjusted)

75mg BIDCrCl 15-30

15mg DailyCrCl 15-50

2.5mg BID2+ of: Age≥80, Weight≤60kg,Cr≥1.5

Do NOT use CrCl>95

30mg Daily CrCl 15-30

VTE Dosing LMWH for 5-10d150mg BID (CrCl>30)

15mg BID x3 wkThen 20mg daily (CrCl≥30)

10mg BID x7 daysThen 5mg BID(2.5mg BID for long-term therapy)

LMWH for 5-10 days60mg Daily30mg Daily ≤60kg or CrCl 15-50

Renal Clearance 80% 33% 25% 35%

Half-life 8-15hr 12 hrs 7-11hrs 10-14 hrs

Drug-drugInteractions

P-Gp Cyp3A4P-Gp

Cyp3A4P-Gp

P-Gp

Betrixaban (BevyxxaR)FDA Approved June 23, 2017To prevent VTE (DVT and PE) for patients who are significantly immobile, and are at increased risk for VTE during and after hospitalization for an acute medical illness - Based on APEX study

F1000Research 6:985, 2017

ACCP 2016 DOAC vs Warfarin vs LMWH

• Favor DOAC over warfarin (Grade 2B) for acute VTE and no cancer– LMWH lead-in needed for dabigatran and edoxaban– Single-drug regimen for rivaroxaban and apixaban

• Favor LMWH over warfarin or DOAC (Grade 2C) for cancer-associated acute VTE (first 3 months)– Reasonable to continue initial anticoagulant after 3

months of therapyCHEST 2016 doi:10.1016/j.chest.2015.11.026

Andexanet Alfa for the Reversal of Factor XaInhibitor Activity

Siegel DM, Curnutte JT, Connolly SJ, et al; NEJM 2015; 373:2413-224

Antifactor Xa level 94% vs 21% (Placebo) for ApixabanAntifactor Xa level 92% vs 18% (Placebo) for Rivaroxaban

Sustained with Bolus Plus Infusion

FDA Approval May 4, 2018

The US Food and Drug Administration (FDA) has approved andexanet alfa(AndexXa, Portola

Pharmaceuticals) as the first and only antidote for patients treated with rivaroxaban and apixaban when the reversal of

anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Andexanet Alfa for the Reversal of Factor XaInhibitor Activity

Sadek M, Vascular Specialist Sept 2020, 7-8

Multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication.

Patients with cancer with symptomatic or incidental acute proximal DVT or PE received oral apixaban (10 mg bid for the first 7 days, followed by 5 mg bid) or subcutaneous dalteparin(200 IU/kg qd for the first month, followed by 150 IU/kg qd). The treatments were administered for 6 months.

Recurrent VTE occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixabangroup and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P=0.60).

Oral apixaban was noninferior to subcutaneous dalteparinfor the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding.

When to Monitor DOACs• Bleeding• Before surgery/procedure with recent DOAC use

(<24hrs, or 48-72hrs if CrCl<30)• Concurrent use of P-gP or CYP3A4-interacting meds• Extremes of body weight• Declining renal function• Potential need for DOAC reversal• Suspected overdose• Assessing compliance (limited by short t1/2)

Baglin T. J Thromb Haemost2013; 11(Suppl 1):122--128

DOAC Lab Monitoring

Anderson and Cifu JAMA 2018; 319:2032-2033

Must ensure calibration for

DOACs

Normal APTT usually indicates drug levels are insignificant; Prolonged APTT suggests that patient has clinically significant drug levels

Negative Anti-Xa assay usually indicates drug levels are insignificant; Prolonged PT/APTT suggests that patient has clinically significant drug levels

Chronic VTE Treatment

-100%-90%-80%-70%-60%-50%-40%-30%-20%-10%

0%

Warfarin(estimated)

Dabigatran Rivaroxaban Apixaban(2.5mg)

Aspirin

Relative Risk Reduction vs Placebo

NEJM 2003; 348:1425-1434. NEJM 2003; 349:631-639. NEJM 2010; 363:2499-2510. NEJM 2013; 368:699-708. NEJM 2013; 368:709-718. Circulation 2014; 130:1062-1071. NEJM 2017; 376: 1211-1222

ACCP guidelines 2016 Tibial DVT: Treatment

In patients with acute isolated distal DVT of the leg: (i) without severe symptoms or risk factors for extension, we suggest

serial imaging of the deep veins for 2 weeks over anticoagulation (Grade 2C)

(ii) with severe symptoms or risk factors for extension, wesuggest anticoagulation over serial imaging of the deep veins(Grade 2C)

In patients with acute isolated distal DVT of the leg who are managed with anticoagulation, we recommend using the same anticoagulation as for patients with acute proximal DVT (Grade 1B)

Calf Vein DVTThe Compression Alone Versus Anticoagulation for Symptomatic Calf Vein Thrombosis Diagnosed by Ultrasonography (CACTUS) trial was performed to assess the safety of withholding anticoagulantion in patients with isolated symptomatic calf vein DVT at low risk for proximal extension/VTE - no personal VTE history or active malignancy.

LMWH did not reduce proximal extension or VTE and resulted in increased bleeding complications. It was underpowered for its endpoints, as only 259 patients enrolled and the calculated power required was 572 patients.

Righini M. J Thromb Haemost. 2007;5 Suppl 1:55-9.Righini M, Galanaud JP, Guenneguez H, et al. Lancet Haematol. 2016;3:e556-e562.

Parisi R, Visona A, Camporese G, et al. Int Angiol. 2009;28:68-72.

Calf Vein DVT

Kuczmik W et al, Thrombosis and Haemostasis DOI DOI https://doi.org/ 10.1055/s-0040-1715646. ISSN 0340-6245

• In those with SVT > 5 cm, use prophylactic dose fondaparinux or LMWH for 45d (2B)

• In those with SVT treated with anticoagulation, suggest fondaparinux (2.5mg) over prophylactic LMWH (2C)

Superficial thrombophlebitis: treatment

Superfical ThrombophlebitisSURPRISE trial, a randomized, open-label trial enrolling 472 patients. A departure from CALISTO which had excluded patients with history of malignancy treated within the last 6 months, the SURPRISE trial was designed to include patients at highest risk for VTE, including those with cancer.

In SURPRISE, patients were included only if they had superficial thrombophlebitis and one of the following risk factors associated with a higher rate of thromboembolic complications: age >65 years, male sex, previous cancer, history of VTE and absence of varicose veins.

When comparing 6-weeks of prophylactic fondaparinux to daily rivaroxaban (10mg qday), rivaroxaban was non-inferior to fondaparinux in the prevention of DVT, PE, and progression or recurrence of SVT.

Rivaroxaban therapy was postulated to be a less expensive and a more patient-friendly.

Decousus H, Prandoni P, Mismetti P, et al. . N Engl J Med. 2010;363:1222-32; Beyer-Westendorf J, Schellong SM, Gerlach H, et al. . Lancet Haematol. 2017;4:e105-e113

Bridging for vascular surgeons

Douketis JD, et al. NEJM 2015; 373(9):823-33

NNH = 53

NNH = 11

Limited Use of Bridging Anticoagulants

<10% of all patientsAF with recent stroke (<3 mo)AF with very high stroke risk (CHADS2=5/6)Recent VTE (<3-12 months)Mechanical Valve (especially MVR)

Venous Thromboembolism in the Context of Chronic Venous

DiseaseMichael Kemp MD, Andrea Obi MD,

Peter Henke MD, Thomas Wakefield MD

Types of Congenital CVD •Klippel-Trenaunay Syndrome (KTS)

• capillary, venous, arterial malformations

• Parkes-Weber Syndrome (PWS)

• capillary, venous, arterial, lymphatic malformations

• KILT Syndrome• Kidney, inferior vena cava

abnormalities, leg thrombosis

SECTION OF VASCULAR SURGERY

Risk of VTE Congenital CVD • Seems to be increased risk of VTE

• KTS• Few higher level studies

• 8-22% incidence of VTE• ~109 and 106-fold increased risk of DVT/PE• Risk independent of pregnancy status

• PWS• Data primarily limited to case reports involving DVTs

• KILT• Characterized by thromboses (typically deep system)

• Children • If no risk factors…evaluate for congenital

abnormalities/syndromes

SECTION OF VASCULAR SURGERY

Non-congenital CVD• Primary versus secondary often not delineated between • VTE risk in primary CVD

• Few studies• 4.7x increased VTE risk• Estimated 2/3 of DVT patients had

primary CVD• 5% occurrence in a retrospective

observational study • More studies needed

SECTION OF VASCULAR SURGERY

Varicose Veins

• Can be primary or secondary • Increased risk of primary VTE

• HR 5.3 in a retrospective cohort study• Risk decreases with age

• OR 4.2 (age 45) versus OR 0.9 (age 75)• Unclear why

• Increases risk of other high-risk groups• Cancer• Surgical patients

• But may not be predictive of VTE recurrence

SECTION OF VASCULAR SURGERY

Post-thrombotic Sydnrome

SECTION OF VASCULAR SURGERY

•Unclear risk of recurrent DVT• One study found 2.6-fold increased risk • Another study found no increased HR

• Indefinite anticoagulation not warranted

Post-thrombotic Syndrome

• Residual vein thrombosis (RVT) may be helpful

• Presence at 3 months: ↑ recurrence (HR 2.03)• ↑ risk despite continued/extended

anticoagulation • 10.4% incidence in those with RVT • 1.4% incidence in those without RVT

• Limitations with standardization • Technician dependent • Patient dependent

SECTION OF VASCULAR SURGERY

Calf muscle pump dysfunction and VTE risk

Andrea T. Obi, Thomas W. Wakefield, Calf muscle pump dysfunction and VTE risk. Blood 137 (23) : 3161-3162, 2021

Copyright © 2021 American Society of Hematology

COVID-19 COAGULOPATHY

Colling ME, Kanti Y. Vasc Med. 2020; 25(5):471-478.

COVID-19 COAGULOPATHY (ICU/Non ICU and D-dimer)• Recent registry study has demonstrated that in 1114 patients with an ICU

subset (n170), symptomatic VTE was seen in 27% (despite VTE prophylaxis)

Piazza G, Campia U, Hurwitz S, et al, J Am Coll Cardiol 76(18): 2060-2072, 2020.• Systematic review and meta-analysis of 66 studies (28,173 patients)

demonstrated VTE prevalence of 40.3% (ultrasound screening) and 9.5% (without ultrasound screening).

• VTE prevalence (overall) of 7.9% (non-ICU) and 22.7% (ICU patients)• VTE prevalence (screening) 23% (non-ICU) and 45.6% (ICU patients)

Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Res Pract Thromb Haemost 2020; 4:1178-1191.

• DVT found in 14.7% (ultrasound screening) in 156 non-ICU patients with elevated D-dimer >1000ng/ml

• DVT found in 85.4% (ultrasound screening) of 48 critically ill patients with 75% isolated distal / 10.4% proximal DVT with marked elevations in D-dimerDemelo-Rodriguez P, Cervilla-Munoz E, Ordieres-Ortega L, et al. Thrombo Res 2020; 192:23-26.

Ren B, Yan F, Deng Z, et al. Circulation 2020; 142:181-183.

COVID-19 COAGULOPATHY (At Discharge and Beyond)• Screening for DVT upon admission to an Inpatient rehabilitation facility

DVT 22% (25/113) with 7.1% (8/113) Proximal• Risk factors – male sex, younger age, and having been on ventilatorKirshblum SC, DeLauter G, Eren F, et al. American Journal of Physical Medicine and Rehabilitation 2021; 100:419-423.

Artifoni M, Danic G, Gautier G, et al. J Thromb Thrombolysis https://doi.org/10.1007/s11239-020-02146-z

• Systematic lower limb venous duplex ultrasonographty performed at hospital discharge or earlier if DVT clnically suspected and Chest CT performed if PE suspected.

• DVT 22.5% (16/71) and PE 10% (7/71) despite adequate prophylaxis predicted by Increased D-dimer

• Following 1877 hospital discharges, 9 episodes of hospital associated DVT within 42 days (0.5%) or rate of 4.8/1000 discharges

• Over 2019 following 18,159 discharges, 56 episodes of hospital associated DVT within 42 days (0.7%)

Roberts LN, Whyte MB, Georgiou L, et al. Blood 2020; 136:1347-1350.

CAC: clinical and laboratory manifestations

Thachil, Cushman, 2020 RPTH: 4; 731-736

Subclinical microthrombi PE/pulm thrombosis/DVT Systemic thrombosis/DIC

Key features of CAC

Connors and Levy. Blood, 2020, 135: 2033-2039

Among noncritically ill patients hospitalizedwith Covid-19, an initial strategy of therapeuticdose

anticoagulation with heparin increased theprobability of survival until hospital dischargewith reduced use of ICU-level organ support ascompared with usual-care thromboprophylaxis.

In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation

with unfractionated or low-molecular-weight heparinwas not associated with a greater probabilityof survival to hospital discharge or a greater

number of days free of cardiovascular or respiratoryorgan support than was usual-care pharmacologic

thromboprophylaxis. The probability thattherapeutic-dose anticoagulation was inferior tousual-care thromboprophylaxis with respect to

these outcomes was high.

March 18, 2021Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care UnitThe INSPIRATION Randomized Clinical TrialINSPIRATION InvestigatorsArticle InformationJAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152

ConclusionsAmong patients with COVID-19 admitted to the ICU, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients with COVID-19 admitted to the ICU.

Anticoagulation in Patients Hospitalized

with COVID-19

Renato D. Lopes, MD, PhDon behalf of the ACTION COALITION

COVID-19 Brazil Investigators

The AntiCoagulaTIon cOroNavirus (ACTION) Trial

www.thelancet.com Published online June 4, 2021 https://doi.org/10.1016/S0140-6736(21)01203-4

Slides provided by Eduardo Ramacciotti

Therapeutic anticoagulation

Followed by rivaroxaban through 30 days, irrespective of duration of hospitalization

TrialDesign

Multicenter, phase IV, randomized clinical trial

PRIMARY OUTCOMEHierarchical analysis of mortality, duration of hospitalization, and

duration of oxygen use through 30 days

Standard of care with in-hospital prophylactic

dose anticoagulation

INCLUSION CRITERIA• Patients aged ≥18 years• Hospitalized with a confirmed

diagnosis of COVID-19 and duration of symptoms related to hospitalization ≤14 days.

• Elevated D-dimer (>ULN) at admission

MAIN EXCLUSION CRITERIA• Indication for therapeutic

anticoagulation at screening• eCrCl <30 ml/min• Platelets <50,000 /mm3

• Use of P2Y12 inhibitor or ASA >100 mg daily

• Very high risk of bleeding

Stable Patients

In-hospital rivaroxaban 20 mg daily

Unstable Patients

In-hospital enoxaparin1mg/kg twice daily

Lopes RD, et al. AHJ, 2021 Randomize

N: 615 patients

Study Flow Diagram

311 randomized to therapeutic anticoagulation311 received intervention as randomized

304 randomized to prophylactic anticoagulation303 received intervention as randomized

1 received therapeutic anticoagulation

Analysis

3331 patients were assessed for eligibility

615 randomized

Follow-up (30 days)

Allocation

Lost to follow-up:1 participant withdrew consent and declined to contribute data

310 included in primary analysis

Lost to follow-up: 0

304 included in primary analysis

2716 excluded1439 did not meet inclusion criteria

523 had more than 14 days of symptoms485 COVID-19 not confirmed410 had normal D-dimer21 were < 18 years old

1007 met exclusion criteria431 had indication for therapeutic anticoagulation205 had eCrCl < 30 ml/min95 had active cancer68 were using P2Y12 inhibitor46 had contraindication for therapeutic anticoagulation41 had previous hemorrhagic stroke/intracranial bleeding36 had INR > 1.526 were pregnant or breastfeeding20 had known HIV infection17 had platelet count < 50,000/mm3

10 were using ASA > 100 mg per day8 were using strong CYP3A4 inducer2 had uncontrolled blood pressure1 had chronic use of NSAIDs1 had DIC

269 declined to participate1 duplicated

Primary Outcome Hierarchical analysis of mortality, duration of hospitalization, and duration of oxygen use through 30 days 34.8%

41.3%

23.9%

0

10000

20000

30000

40000

Wins Ties

Mat

ches

Group: Therapeutic Prophylactic

WR [95% CI] = 0.86 [0.59-1.22]

Safety OutcomesSafety Outcome

Therapeutic(N=310)

Prophylactic(N=304)

EffectMeasure

Effect(95% CI)

ISTH major bleeding or clinically relevant non-major bleeding 26/310 (8.4%) 7/304 (2.3%) Relative Risk 3.64 (1.61–8.27)

Major bleeding 10/310 (3.2%) 4/304 (1.3%) Relative Risk 2.45 (0.78–7.73)

Clinically relevant non-major bleeding 16/310 (5.2%) 3/304 (1.0%) Relative Risk 5.23 (1.54–17.77)

Any bleeding 36/310 (11.6%) 9/304 (3.0%) Relative Risk 3.92 (1.92–8.00)

Net clinical benefit* 56/310 (18.1%) 47/304 (15.5%) Relative Risk 1.17 (0.82–1.66)*Net clinical benefit is defined as composite outcome including any composite thromboembolic outcome, all-cause mortality, and ISTH definitions of major or clinically relevant non-major bleeding.

ConclusionIn patients hospitalized with COVID-19 with elevated D-dimer levels, initial in-hospital therapeutic anticoagulation with rivaroxaban 20 mg once daily for stable patients or enoxaparin for unstable patients followed by rivaroxaban through 30 days did not improve clinical outcomes and increased bleeding compared with in-hospital prophylactic anticoagulation.

Copyright © 2021 American Society of Hematology

DRAFT RECOMMENDATION (UPDATED JULY 8, 2021)

The ASH guideline panel suggests not using anticoagulant outpatient

thromboprophylaxis in patients with COVID-19 who are being discharged from the

hospital and who do not have suspected or confirmed VTE or another indication for

anticoagulation (conditional recommendation based on very low certainty in the

evidence about effects).

Remarks: An individualized assessment of the patient’s risk of thrombosis and bleeding and

shared decision-making is important when deciding whether to use post-discharge

thromboprophylaxis. Validated risk assessment models to estimate thrombotic and bleeding

risk in COVID-19 patients following hospital discharge are not available. The panel

acknowledged that post-discharge thromboprophylaxis may be reasonable in patients judged

to be at high thrombotic risk and low bleeding risk.

Design: Prospective, randomized, open-label, controlled, multi-center trial

No anticoagulation

Rivaroxaban (10 mg/day)

Day 35±4

R

Day 75 (phone call)

~320 COVID+Medically Ill hospitalized

with IMPROVE ≥4or

IMPROVE 2-3 with Ddimer >500 ng/mL receiving LMWH or

UFH Discharge

Screening

Follow-up

Doppler US + pulmonary angioCTat day 35+4

Primary endp: symptomatic VTE, VTE-related death, VTE detected by mandatory bilateral lower limbs venous duplex scan and pulmonary angioCT on day 35±4 post-hospital discharge and (myocardial infarction [MI], non-hemorrhagic stroke, major adverse limb events [MALE] and cardiovascular [CV] death + all cause death up to day 35±4 post-hospital discharge.

Power: 80%, Two sided alpha 0.05 (Control 15%, Treatment 5%; 67% RRR)

STUDY DESIGN

Rivaroxaban is not approved for patients admitted or discharged for an acute medical illness by EMEA

KEY INCLUSION AND EXCLUSION CRITERIA

KEY INCLUSION CRITERIA

Patients ≥ 18 years hospitalized for minimum of 3 days with standard dose thromboprophylaxis (LMWH, fondaparinux or UFH) prior to randomization for SARS-CoV-2 infection (COVID-19)

Total modified IMPROVE VTE Risk Score ≥ 4 OR total modified IMPROVE VTE Risk Score 2 or 3 and D dimer > 500 ng/ml during index hospitalization

KEY EXCLUSION CRITERIA

Bleeding Risks Any bleeding within 3 months Surgery, biopsy or trauma 4 weeks prior or

planned Active gastroduodenal ulcer Active cancer

Required anticoagulation after discharge Use of dual antiplatelet therapy during the

index hospitalization Creatinine clearance < 30 ml/min Concomitant Medications

Combined P-gp and strong CYP3A4 inhibitors

Combined P-gp and strong CYP3A4 inducers

CLINICAL OUTCOMES

PRIMARY OUTCOMEComposite of symptomatic VTE, VTE-related death, and VTE detected at bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram and symptomatic arterial thromboembolism, myocardial infarction (MI),

non-hemorrhagic stroke, major adverse limb event (MALE), and cardiovascular (CV) death at day 35

Clinical outcomes were adjudicated by an independent committee in a blinded fashion

SECONDARY OUTCOMES

Symptomatic and fatal VTESymptomatic VTE + all cause mortality

Symptomatic VTE, MI, stroke and cardiovascular death

KEY SAFETY OUTCOME

Incidence of major bleeding according to ISTH criteria

9.43%

0%

3.14%

0%0

1

2

3

4

5

6

7

8

9

10

Primary endpoint* Major bleedingControl Rivaroxaban

PRIMARY EFFICACY/SAFETY OUTCOMES

*Composite of composite of symptomatic VTE, VTE-related death, asymptomatic VTE (Doppler and AngioCT scan) and symptomatic ATE, MI, non-hemorrhagic stroke, (MALE), and cardiovascular death at day 35.

RRR =67%

RR = 0.33 (0.13—0.90)p=0.03 (superiority)NNT = 16

Secondary efficacy outcomes RIVAROXABAN(N = 159)

CONTROL(N = 159)

RELATIVE RISK(95% CI)

Symptomatic + fatal VTE 1/159 (0.63%) 8/159 (5.03%) 0.13 (0.02 –0.99)

Symptomatic VTE + all cause mortality 4/159 (2.52%) 9/159 (5.66%) 0.44 (0.14 –1.41)

A composite of Symptomatic VTE, MI, stroke and cardiovascular deaths 1/159 (0.63%) 9/159 (5.66%) 0.11 (0.01 –0.87)

Components of the primary outcomeSymptomatic DVT 0 3 (1.89%) 0.14 (0.01 – 2.74)

Symptomatic PE 1 (0.63%) 2 (1.26%) 0.50 (0.05 –5.46)

Fatal PE 0 3 (1.89%) 0.14 (0.01 – 2.74)

Asymptomatic DVT detected at duplex scan 3 (1.89%) 1 (0.63%) 3.00 (0.32 –28.53)

Asymptomatic PE detected at CT pulmonary angiogram 1 (0.63%) 4 (2.52%) 0.25 (0.03– 2.21)

Symptomatic arterial thrombosis 0 1 (0.63%) 0.33 (0.01 –8.12)

Myocardial infarction 0 0 -

Non-hemorrhagic stroke 0 0 -

Major adverse limb event (MALE) 0 0 -

Cardiovascular deaths 0 1 (0.63%) 0.33 (0.01 –8.12)

SECONDARY EFFICACY OUTCOMES

CONCLUSION

In patients discharged after hospitalization due to COVID-19 with increased IMPROVE score, thromboprophylaxis with rivaroxaban 10 mg once-daily for 35 days improved clinical outcomes, without increasing bleeding compared with

no out-of-hospital anticoagulation

Arepally BM and Ortel TL, Blood (First Edition), 2021

VITT

In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.JAMA 326:332-338, 2021

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