thrombosis - care™ education

Thrombosis

Wendy Lim, MD, MSc, FRCPC

Professor, Department of Medicine, Division of Hematology & ThromboembolismMcMaster University

Disclosures*

Consultant: Pfizer, Portola PharmaceuticalsHonoraria: BMS-Pfizer Alliance, Novartis, Pfizer, Pharmacosmos

*2018 - present

Overview

• To highlight key studies in venous thromboembolism (VTE) presented at ASH 2019– VTE and cancer: Bleeding risk assessment for 1) patients with cancer receiving

prophylactic anticoagulation; 2) in patients with polycythemia vera and anticoagulant/antiplatelet use

– VTE risk stratification in patients with cancer and VTE– Bleeding risk using the PAUSE perioperative DOAC strategy

• To provide a Canadian/Ontario perspective on these developments and their impact on clinical practice

• Venous thromboembolism (VTE) is common in patients with cancer– Occurs in 4-20% of cancer patients1

• VTE in cancer patients contributes to increased morbidity and mortality– Associated with higher rates of recurrent VTE and bleeding compared to non-cancer

patients3

• Treatment and prevention of cancer-associated thrombosis is an important part of cancer treatment

1-Khorana et al. J Thromb Haemost 2007;5:632. 2-Sorensen et al. N Engl J Med 2000;343:1846. 3-Prandoni et al. Blood 2002;100:3484.

Cancer and VTE

Cancer and VTEFrom ASH 2018 • CASSINI (+ AVERT) demonstrated that prophylactic dose DOACs could be

used to prevent thrombosis in high-risk ambulatory cancer patients (compared to placebo x 6m)*– Apixaban 2.5 mg bid reduced VTE, increased major bleeding; Rivaroxaban 10

mg od decreased VTE and death during the intervention period (not statistically significant overall)

From ASH 2017 • HOKUSAI-VTE and SELECT-D demonstrated that DOACs were noninferior

to LMWH for treatment of cancer-associated thrombosis**– Edoxaban had lower rVTE but higher major bleeding; rivaroxaban had lower

rVTE but highter CRNMB, both compared to dalteparin

*Carrier M et al. N Engl J Med 2019;380:711-19. Khorana A et al. N Engl J Med 2019; 380:720-28.

**Raskob G et al. N Engl J Med 2018;378:615-24. Young AM et al J Clin Oncol 2018;36:2017-23

Khorana Score

Khorana A et al, Blood 2008

Khorana Score – cumulative 6 month VTE risk 0: 1.5%1: 3.8%2: 9.6%

≥3: 17.7%

Cancer and VTE709: Bleeding Risk in a Cohort of Ambulatory Cancer Patients Receiving Outpatient Prophylactic Anticoagulation for Venous Thrombosis Prevention• Session: 332. Anticoagulation and Antithrombotic Therapy: Bleeding Outcomes

634: Enhanced VTE Risk Stratification in Ambulatory Patients with Cancer• Session: 331. Pathophysiology of Thrombosis: Cancer-Associated and Pediatric Thrombosis

168: Risk of Hemorrhage in Patients with Polycythemia Vera Exposed to Aspirin in Combination with Anticoagulants: Results of a Prospective, Multicenter, Observational Cohort Study (REVEAL)• Session: 332. Anticoagulation and Antithrombotic Therapy I

709: Bleeding Risk in a Cohort of Ambulatory Cancer Patients Receiving Outpatient Prophylactic Anticoagulation for Venous Thrombosis Prevention

Andrew B Wilks*, Daniel Douce, Steven Ades, Mary Cushman, Neil A. Zakai, and Chris E. Holmes

• Bleeding risk in prophylaxis trials ~2% over the first 6 months• Utility of prophylactic anticoagulation (AC) depends on balance of bleeding and

thrombosis in an individual patient• Single-center prospective cohort study, enrolled consecutive ambulatory patients

initiating cancer-directed treatment already on or starting AC– Risk stratified using Khorana score; ≥3 were offered prophylactic AC

• Evaluated risk of major bleeding using prophylactic AC over first 6 months of therapy – Measured major and minor bleeding events by billing code screening, confirmed by review of the

medical record– Used logistic regression to compare odds of developing a major bleed within 6 months in those

who received prophylactic AC compared to those that did not



• N = 1,210 patients; enrolled from October 2015 - June 2018– Women 52.9%; Cancer types: gastrointestinal 22%, lung 18%, breast 16%– Khorana score 0 = 32%, 1-2 = 58%, ≥3 = 9%

• N=421 (35%) were on any AC (LMWH or DOAC) during this time; 282/421 (67%) prophylactic AC; 139/421 (33%) therapeutic AC– Prophylaxis: Apixaban 41% (n=107); Rivaroxaban 2.3% (6); Enoxaparin 45.7% (119), other

heparins 19.2% (50)

• Rate of bleeding within first 6 months of cancer therapy:– Major bleeding 2.33% (n=27)– Minor 1.81% (22)– Bleeding on prophylactic AC 2.8% (n=8)– Bleeding on therapeutic AC 4.3% (n=6)



• During first 6 months of therapy, prophylactic AC associated with increased risk of major bleeding; similar to clinical trials– Age, higher Khorana score not associated with increased risk of major bleeding

• Men, lung cancer may have increased risk of major bleeding while on prophylactic AC

Within 6 months of initiating cancer treatment OR (95% CI)

Developing major bleed on any AC 1.78 (0.82-3.88)

Developing major bleed on prophylactic AC 1.49 (0.64-3.48)

Predictors of bleeding OR (95% CI)

Major bleeding while of prophylactic AC- Lung cancer (major bleeding)- Male (compared to women)- Increasing age (by 1 year)- Khorana score >3 (compared to <3)

2.81 (1.27-6.25)0.20 (0.07-0.52)1.02 (0.99-1.06)1.04 (0.73-1.50)

634: Enhanced VTE Risk Stratification in Ambulatory Patients with CancerJoseph R. Shaw, Ranjeeta Mallick, Marc Carrier, Anton Ilich, Nigel S. Key, Philip S. Wells

• VTE risk stratification may be enhanced with CATS score– Incorporates additional points for elevated biomarkers (d-dimer, p-selectin) to Khorana

score• Assessed VTE incidence in patients with Khorana ≥2+↑biomarkers• Analysed AVERT population; D-dimer and p-selectin measured at

randomization– 1 additional point for D-dimer ≥ 2.06 ug/mL; p-selectin ≥ 44.5 ng/mL (>75th percentile)

• Cumulative 6 month VTE incidence calculated using Kaplan-Meier analysis for Khorana and CATS score

634: Enhanced VTE Risk Stratification in Ambulatory Patients with CancerJoseph R. Shaw, Ranjeeta Mallick, Marc Carrier, Anton Ilich, Nigel S. Key, Philip S. Wells

Khorana ≥3 CATS ≥4

6 month cumulative incidence of VTE 13% (95% CI 7-23) 20% (11-35)

Bleeding- Overall- Major

7 (8.1%; 2.4-13.9%)2 (2.3%; 0-5.5%)

7 (10.6%; 3.2-18.0%)2 (3.03%; 0-7.17%)

Risk score ≥3

Risk score 2

Risk score ≥4

Risk score 2

Risk score 3

168 Risk of Hemorrhage in Patients with Polycythemia Vera Exposed to Aspirin in Combination with Anticoagulants: Results of a Prospective, Multicenter, Observational Cohort Study (REVEAL)

Jeffrey I. Zwicker, David S. Lessen, Philomena Colucci, Dilan Paranagama, Michael R. Grunwald

• ASA is used for primary thromboprophylaxis in polycythemia vera (PV), given increased risk of bleeding and thrombosis

• ASA frequently discontinued at time of AC initiation due to increased bleeding risk • REVEAL: prospective, non-interventional cohort study of patients with PV, 204 centres

in US; evaluated bleeding rates in patients with PV on AC and ASA– Included bleeding data from retrospective data up to 6 months before enrollment– Bleeding events graded

• Subgroups (AC only, ASA only, AC+ASA, neither) defined by treatments received prior to enrollment; determined bleeding event rates in each subgroup, association between bleeding risk and AC use assessed with Cox proportional hazards model



• N=2510– ASA alone = 1490 (59.4%)– AC alone = 183 (7.3%)– AC + ASA = 108 (4.3%)

• Median follow-up 2.3 years (range 0-3.6) • Most common anticoagulants used: warfarin, rivaroxaban, apixaban

Characteristic

Median age, years 67 (range 22-95)

Men 54.2%

Hypertension 56.0%

History of thrombosis 19.9%



• AC+ASA in the post-enrollment period had >4-fold increase in bleeding (HR [95% CI] = 4.22 [2.57, 6.94]; P <0.0001) compared with patients on single agent or no treatment; risk of severe bleeding significantly higher for same patients (HR = 3.06 [1.35, 6.95]; P=0.0074).

• Combination AC+ASA associated with increased bleeding compared to ASA alone; caution in using antiplatelet agents with AC in these patients

Bleeding-GI; cutaneous; GU

110 (4.4%)51 (46.4%); 27 (24.5%); 12 (10.9%)

‘Severe’ bleeding-Hospitalization; Fatal

46 (1.8%)38 (82.6%); 7 (15.2%)

Any hemorrhage (per 100 pt-yrs)- ASA- AC + ASA

2.0 (1.64, 2.39)1.5 (1.09, 1.93)

7.9 (4.17, 11.56)

3 year cumulative incidence for:-Any hemorrhage; severe hemorrhage 22.1% (12.42, 33.52);3.0% (0.80, 7.81)

Perioperative management

• Anticoagulant management around the time of invasive procedures or surgeries is not standardized

• BRIDGE trial demonstrated in patients with atrial fibrillation (AF) that no bridging was noninferior to LMWH bridging in preventing arterial thromboembolism (TE) and decreased risk of major bleeding*

• PAUSE trial evaluated a standardized perioperative strategy in patients with AF based on direct oral anticoagulant (DOAC) PK properties and procedure-associated bleeding risk**

*Douketis et al. N Engl J Med 2015;373:823. **Douketis et al. JAMA Intern Med 2019; Aug

PAUSE: Perioperative management protocol

710 Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) StudyAlfonso J Tafur, Na Li, Nathan Clark, Sam Schulman, Alex Spyropoulos, Joseph A Caprini, James Douketis

• PAUSE study population, n=3007; assessed factors associated with perioperative bleeding events

• Bleeding defined as major + clinically relevant non-major (MB/CRNM) as per ISTH criteria

MB/CRNM rates (up to 30 days post procedure): • Apixaban n=1,257; 3.02%• Dabigatran n=668; 2.84%• Rivaroxaban n=1,082; 4.16%Factors significantly associated with MB/CRNMB (multivariate analysis)• Hypertension: OR 1.81, 95%CI 1.07-3.07; p=0.027• Prior bleed or bleed predisposition: OR 1.62, 95% CI 1.02-2.58; p=0.043 • Active cancer: OR 2.30, 95% CI 1.10-4.81, p=0.026

710 Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) StudyAlfonso J Tafur, Na Li, Nathan Clark, Sam Schulman, Alex Spyropoulos, Joseph A Caprini, James Douketis

• Surgery bleeding risk was significantly associated with MB/CRNM (low vs high, OR 0.56, 95% CI 0.36-0.86; p=0.008) in univariate analysis only

• Lower MB/CRNM bleeding with female sex• DOAC level (available for 84.5%) drawn prior to surgery was not associated

with bleeding risk

710 Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study

Alfonso J Tafur, Na Li, Nathan Clark, Sam Schulman, Alex Spyropoulos, Joseph A Caprini, James Douketis

• Exploratory analyses only – no modification of protocol suggested based on these results (still based on surgical bleed risk)

• Multivariate model had low performance; hypertension is the only modifiable pre-surgical risk - ?role for management

• No routine DOAC level monitoring prior to surgery

Ontario and Canadian perspective• Prevention and treatment of CAT continues to evolve• LMWH and DOACs are used first line for VTE treatment

– Apixaban, rivaroxaban and edoxaban covered in Ontario (ODB) x 6 months for VTE treatment, not for extended treatment

– LMWH covered for up to 12 months• Coverage of VTE prophylaxis in cancer patients is an ongoing issue, limiting

uptake?– Prophylactic dose DOACs not covered by ODB or LU code for this indication

• Key perioperative anticoagulation studies conducted from Canadian investigators and centres, consider use ofPAUSE protocol for perioperative management

• Results can be used to standardize practice and guidelines

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