chronic care management: focus on …...chronic care management: focus on anticoagulation...

CHRONIC CARE MANAGEMENT:

FOCUS ON ANTICOAGULATION

FRIDAY/1:15-3:15PM

ACPE UAN: 0107-9999-20-029-L01-P 0.2 CEU/2.0 hr

Activity Type: Application-based

Learning Objectives for Pharmacists:

Upon completion of this CPE course participants should be able to:

1. Identify candidates for extended anticoagulation therapy following venous thromboembolism (VTE) and

select corresponding direct acting anticoagulant (DOAC) regimen.

2. Discuss the role of DOACs in prevention and treatment of VTE in patients with cancer.

3. Evaluate clinical trials assessing the role of direct oral anticoagulants in patients with stable cardiovascular

disease.

4. Identify the role of direct oral anticoagulants in patients with atrial fibrillation who have undergone a

percutaneous coronary intervention.

5. Recommend appropriate monitoring parameters for patients on DOAC therapy based on risk stratification.

Speakers: Andrew Miesner, PharmD, BCPS

Andy received his Doctorate of Pharmacy at Drake of University and completed a pharmacy practice

residency at Iowa Methodist Medical Center in Des Moines, Iowa. He began teaching at Drake

University College of Pharmacy and Health Sciences in 2008 is currently an Associate Professor of

Pharmacy Practice. He maintains a clinical practice site at Broadlawns Medical Center in Des Moines

where he previously managed the Internal Medicine Anticoagulation Clinic. He currently serves as the

clinical pharmacist for the Internal Medicine Teaching Service and the pharmacist leader of

Broadlawns Antimicrobial Stewardship Program. Andy is a Board Certified Pharmacotherapy Specialist.

Tadd Hallwig, PharmD, BCPS, FASHP

Tadd Hellwig graduated from the Texas Tech University Health Sciences Center School of Pharmacy in

2006 and completed a Pharmacy Practice Residency at Christiana Care Health System in Newark, DE

in 2007. He is currently a Professor of Pharmacy Practice at the South Dakota State University College

of Pharmacy and Allied Health Professions. Tadd holds a clinical practice site in Internal Medicine at

Sanford USD Medical Center in Sioux Falls, SD. His major research interests include anticoagulation,

infectious disease, and liver disease. He has completed numerous scholarly projects in these areas

that have resulted in publications, poster presentations, and speaker invitations at regional and

national pharmacy meetings.

Sara Wiedenfeld, PharmD, BCPS

Sara Wiedenfeld joined the University of Iowa College of Pharmacy as an Assistant Clinical Professor

in 2014. She practices in family medicine at Siouxland Medical Education Foundation. She is a 2007

graduate of Drake University and completed a PGY1 residency at Siouxland Medical Education

Foundation. Prior to joining the University of Iowa, she worked as a clinical pharmacist at Mercy

Medical Center-Sioux City. Her interests include primary care and women’s health.

Speaker Disclosure: The speakers report no actual or potential conflicts of interest in relation to this CPE

activity. Off-label use of medications will be discussed during this presentation.

#RxExpo20

Chronic Care Management: Focus on Anticoagulation

Andrew Miesner, PharmD, BCPS

Associate Professor of Pharmacy Practice

Drake University College of Pharmacy & Health Sciences

#RxExpo20

Disclosure

• Dr. Miesner reports no actual or potential conflicts of interest associated with this presentation

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Learning Objectives

1. Identify candidates for extended anticoagulation therapy following venous thromboembolism (VTE) and select corresponding direct acting anticoagulant (DOAC) regimen.

2. Discuss the role of DOACs in prevention and treatment of VTE in patients with cancer.

#RxExpo20

A slide from an Expo a decade ago…

• Some things never change.

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Extended Anticoagulation for Venous Thromboembolism

THE ROLE FOR DIRECT ACTING ORAL ANTICOAGULANTS

#RxExpo20

A completely made up case…

• CB is a 35-year-old male who comes to your Thrombosis Management Clinic. He had an unprovoked pulmonary embolism about 8 months ago. He has been on rivaroxaban 20mg daily ever since.

• After a round of golf with some friends he wonders if he still needs to take rivaroxaban because he feels great and asks your opinion.

• This was his first VTE event. He is currently on rivaroxaban 20mg daily and no other medications. You consider him low risk for bleeding. He rarely misses doses of his medication and is open to all options. Which is the best option for CB?

A. Decrease rivaroxaban to 10mg dailyB. Stop rivaroxaban and draw a D-dimer in 4 weeksC. Stop rivaroxaban and start aspirin daily

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Venous Thromboembolism (VTE) • 3rd leading cause of vascular disease worldwide

• Lifetime risk of VTE = 8% after age 45• Approximately 1/3rd pulmonary embolism, 2/3rd deep vein thrombosis• PE associated with approximately 20% mortality risk

• Recurrent VTE occurs in 30% of patients within 5 years of an unprovoked VTE

• 10% recurrence in first 6-12 months after stopping anticoagulation

1. Di Nisio M, et al. Lancet. 2016;388(10063):3060‐73.

#RxExpo20

Anticoagulation in VTE• Standard of care for non-cancer associated VTE remains oral anticoagulants for

at least 3 months for initial VTE episode• Historically injectable anticoagulant bridged to warfarin

• 2016 AT10 guidelines recommend four Direct-Acting Oral Anticoagulants (DOACs) - dabigatran, rivaroxaban, apixaban, edoxaban – over warfarin (Grade 2B)2

• Weak recommendation based on slightly decreased risk of major bleeding in pooled analysis of Phase III trials

• Statistically significant only for rivaroxaban (8/1000 fewer) and apixaban (13/1000 fewer)

• DOACs (combined – 65.6%) have now overtaken warfarin in prescriptions for VTE among commercially insured patients3

2. Kearon C, et al. CHEST. 2016;149(2):315‐52.3. Nathan AS, et al. Circ Cardiovasc Qual Outcomes. 2019;12:e005600.

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Extended Anticoagulation in VTE• “Extended treatment” = additional treatment after initial treatment phase with no

scheduled stop date• Distinct from “longer time-limited” treatment (i.e. 6, 12, 18, 24 months)

• 2016 AT10 guideline recommendation summary2

• Provoked VTE: 3 months recommended over extended therapy• Similar recommendations for distal DVT and proximal DVT and PE

• Unprovoked VTE: extended anticoagulant therapy recommended if low/moderate bleed risk; 3 months if high bleeding risk

• Similar recommendations for both first and second VTE, with High Grade evidence for extended therapy in second event

• In patients who receive extended therapy, there is no need to change the choice of anticoagulant after the first 3 months unless patient factors change

• Continuing use of extended therapy should be reassessed periodically• In patients with an unprovoked VTE who plan to stop anticoagulation, aspirin is recommended if not

contraindicated

2. Kearon C, et al. CHEST. 2016;149(2):315‐52.

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Bleeding risks in VTE2

Extended therapy time frame

• Low risk = 0 risk factors• 0.8% per year

• Moderate risk = 1 risk factor• 1.6% per year

• High risk = 2+ risk factors• >6.5% per year

2. Kearon C, et al. CHEST. 2016;149(2):315‐52.

Age >65 Liver Failure Poor anticoagulant control

Age >75* Thrombocytopenia Reduced functional capacity

Previous bleeding

Previous Stroke Recent surgery

Cancer Diabetes Frequent falls

Metastaticcancer*

Anemia Alcohol abuse

Renal Failure Antiplatelet therapy

NSAID use

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Extended Anticoagulation in VTE• 2017 Cochrane review of first unprovoked VTE

• 6 studies of extended anticoagulation in 3436 patients • Rivaroxaban, warfarin, and aspirin compared to placebo; Rivaroxaban compared to aspirin• Other DOAC trials generally included recurrent VTE

• Non-significant decrease in recurrent VTE (OR 0.63, 95% CI 0.38-1.03)• No differences in mortality, major or non-major bleeding, stroke, or MI either

• Inclusion of aspirin likely influenced overall results (more recurrence than placebo)

• Rivaroxaban lower VTE recurrence rate than aspirin (OR 0.28, 95% CI 0.15-0.54)

4. Robertson L, et al. Cochrane Database Syst Rev. 2017;12:CD011088.

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DOACs in Extended Therapy• Rivaroxaban

• EINSTEIN-Extension study – 20105

• Rivaroxaban 20mg vs placebo for 6-12mo after treatment for acute DVT/PE for 6-12mo• Recurrent VTE occurred in 1.3% of rivaroxaban (HR 0.18; 95% CI 0.09-0.39) – NNT 18 • Major/clinically relevant bleeding in 6% of rivaroxaban (HR 5.19 95% CI 2.3-11.7) – NNH 21

• EINSTEIN CHOICE – 20176

• Rivaroxaban 20mg vs 10mg vs Aspirin 100mg daily 12mo after treatment for acute DVT/PE for 6-12mo

• VTE: 20mg - 1.5%, 10mg – 1.2%, Aspirin – 4.4% (both doses vs aspirin, p<0.001), NNT 32• Major/clinically relevant bleeding: 20mg – 3.3%, 10mg – 2.4%, Aspirin – 2.0% (not significant)

5. The EINSTEIN Investigators. N Engl J Med. 2010; 363:2499‐5106. Weitz JI, et al. N Engl J Med. 2017;376:1211‐22.

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DOACs in Extended Therapy• Dabigatran

• RE-SONATE (placebo) and RE-MEDY (vs warfarin) – 2013 7

• RE-MEDY trial arm considered at “increased risk for recurrence”• Treated 3-18mo prior to enrollment then assigned to Dabigatran 150mg BID,

warfarin, or placebo for variable durations (6-36mo)

• Recurrent VTE - Dabigatran non-inferior to warfarin (1.8% vs 1.3%) (HR 1.44; 95% CI 0.78-2.64)

• Major bleeding not different (p=0.06), but Major/clinically relevant bleeding higher in warfarin (HR 0.54 95% CI 0.41-0.71) – NNH 22

• TTR with warfarin = 65.3%

• Acute coronary syndrome higher in dabigatran group (0.9% vs 0.2%, P=0.02)7. Schulman S. N Engl J Med. 2013; 368:709‐18.

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DOACs in Extended Therapy• Apixaban

• AMPLIFY-EXT – 20138

• Apixaban 5mg BID vs 2.5mg BID vs placebo for 12mo after 6-12mo of initial treatment for VTE

• Both doses superior to placebo for primary outcome of Recurrent VTE or Death – 5mg (4.2% - NNT = 14), 2.5mg (3.8%; NNT = 13), placebo (11.6%); no significant difference between doses

• Major/clinically relevant bleeding no different from placebo

• Edoxaban• Post-hoc analysis of the Hokusai-VTE, originally studied for 3-12mo, but analysis treated

first 3mo as “treatment” and analyzed each 3mo period after as “extension”9

• Edoxaban non-inferior to warfarin in recurrent VTE in 3-12mo time frame (0.3% vs 0.4%), but Major Bleeding was lower (0.3% vs 0.7%, HR 0.45 95% CI 0.22-0.92) – NNT 250

8. Agnelli G, et al. N Engl J Med. 2013; 368:699‐708.9. Raskob G, et al. Lancet Haematol. 2016;3:e228‐36

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Who’s really at risk though?• Most DOAC trials enrolled patients that were equipoise regarding

continuation• How do we predict who is most likely to have another event to guide our

pharmacotherapy?

• Prediction tools for unprovoked VTE• Residual vein thrombosis on ultrasound?

• Predicts recurrence overall, but not for unprovoked• Genetic thrombophilia?

• Risk of initial VTE, poor predictor of risk for recurrence• HERDOO2 score• DASH score

#RxExpo20

Predicting Recurrent VTEHERDOO2 10

• HER – hyperpigmentation, edema, or redness in either leg

• 1 point for any post-thrombotic sign

• D-dimer >250• 1 point

• Obesity (BMI >30)• 1 point

• Older age (>65)• 1 point

DASH 11

• D-dimer >500ng/mL - 4 weeks after stopping anticoagulation

• 2 points

• Age < 50• 1 point

• Sex – male• 1 point

• Hormonal therapy at onset• Negative 2 points

10. Rodger MA, et al. BMJ. 2017;356:j106511. Tosetto A, et al. J Thromb Haemost. 2017;15:1963‐70.

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Predicting Recurrent VTEHERDOO2 10

• Score >2 considered high risk• Anticoagulation should be continued

• Validated a prospective cohort• Low risk who stopped anticoagulation = 3%

recurrence• High risk who stopped anticoagulation =

8.1% recurrence• High risk who continued = 1.6% recurrence

• Meant to be only used in females >50 years, assumes all males are high risk

DASH 11

• Score of >2 considered high risk• Anticoagulation should be continued

• 2 year recurrence:• 0 points = 5.9%• 1 point = 8.4%• 2 points = 11.1%

• Can be used in either men and women

• Best validation in those >65 years10. Rodger MA, et al. BMJ. 2017;356:j106511. Tosetto A, et al. J Thromb Haemost. 2017;15:1963‐70.

#RxExpo20

DOAC Summary in Extended TherapyDOAC “Treatment”

Dose“Extended”

DoseExtended comparator

FDA Approval

Other clinical considerations

Dabigatran 150mg BID (LMWH/UFH

bridge)

150mg po BID Warfarin and placebo

Yes + Direct comparison to warfarin, lower bleeds in extended treatment‐ Increased discontinuation due to dyspepsia‐ Avoid if Coronary Disease‐ Avoid if <30mL/min

Rivaroxaban 15mg BID x21d, then 20mg daily

10mg daily Placebo and20mg dose

Yes + Desire for once daily dosing‐ Must take with food‐ Avoid if <15mL/min or Child‐Pugh B or C

Apixaban 10mg BID x7d, then 5mg BID

2.5mg BID Placebo and 5mg dose

Yes + Lower GI bleed risk than other DOACs‐ No renal adjustment recommended in VTE,

caution if <25mL/min; Avoid in Child‐Pugh C

Edoxaban 60mg daily (LMWH/UFH

bridge)

60mg daily Warfarin No + Desire for once daily dosing‐ Decrease dose to 30mg daily if 15‐50mL/min;

Avoid if CrCL <15mL/min; Avoid >95ml/min?;Avoid in Child‐Pugh B or C

12. Micromedex.

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A completely made up case…

• CB is a 35-year-old male who comes to your Thrombosis Management Clinic. He had an unprovoked pulmonary embolism about 8 months ago. He has been on rivaroxaban 20mg daily ever since.

• After a round of golf with some friends he wonders if he still needs to take rivaroxaban because he feels great and asks your opinion.

• This was his first VTE event. He is currently on rivaroxaban 20mg daily and no other medications. You consider him low risk for bleeding. He rarely misses doses of his medication and is open to all options. Which is the best option for CB?

A. Decrease rivaroxaban to 10mg dailyB. Stop rivaroxaban and draw a D-dimer in 4 weeksC. Stop rivaroxaban and start aspirin daily

Good… fits with ACCP guidelines.

Very reasonable… can calculate DASH.

OK option in the guidelines… select this if he prefers to stop.

#RxExpo20

Treatment and Prevention of Cancer-Associated VTE

THE ROLE FOR DIRECT ACTING ORAL ANTICOAGULANTS

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Another case…

• CC, a 66 year-old-female patient is admitted to your hospital after experiencing a proximal DVT. She has stage III adenocarcinoma of the colon and has recently started FOLFIRI.

• The hospitalist service starts her on dalteparin, but at an excellent CE program you recall learning about a change in treatment recommendations related to CA-VTE.

• Prior to discharge you would:A. Counsel her on administration of dalteparin and continue at least 6moB. Switch to dalteparin to rivaroxabanC. Switch dalteparin to edoxaban after 5 days

#RxExpo20

Cancer-Associated VTE

• Cancer-associated VTE (CA-VTE) has an annual incidence of 0.5%-20% depending on cancer type13

• Associated with a 2-6x higher mortality rate

• Anticoagulation in CA-VTE can be complex• Up to 6x higher risk of bleeding• Up to 4x higher risk of recurrence despite anticoagulation• Loss of dietary intake complicates warfarin use• Antineoplastics may contribute to both thrombotic risk and bleeding risk• Standard of care (LMWH) requires daily injections

13. Ay C, et al. Ann Oncol. 2019;30:897–907.

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Cancer-Associated VTE• 2016 AT10 Guidelines2

• First 3 months anticoagulant therapy: LMWH over warfarin or DOACs • Extended therapy recommended regardless of bleed risk

• 2019 ASCO Guidelines14

• Initial (i.e. 5-10 days) anticoagulation: LMWH, UFH, fondaparinux, or rivaroxaban• LMWH preferred over UFH unless renal impairment

• LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists

• Warfarin may be used if LMWH or DOACs are not accessible• Increased major bleed risk with DOACs (especially GI or GU cancers)

• LMWH, DOACs, or warfarin may be offered beyond 6 months to select patients with active cancer (metastatic disease or ongoing chemotherapy)

2. Kearon C, et al. CHEST. 2016;149(2):315‐52.14. Key NS, et al. J Clin Oncol. 2019;37:JCO1901461.

#RxExpo20

DOACs in Cancer-Associated VTE• 2018 Cochrane Review

• 16 trials of VKAs, LMWH, and DOACs in CA-VTE• LMWH reduces recurrent VTE vs VKAs (RR 0.58, 95% CI 0.43-0.77; 53/1000

fewer), but no difference in mortality or major bleeding• DOACs did not reduce recurrent VTE vs VKAs (RR 0.66, 95% CI 0.33-1.31),

bleeding, or mortality • DOACs did not reduce recurrent VTE at 12mo vs LMWH (RR 0.69, 95% CI

0.47-1.01), but increased major bleeding (RR 1.71, 95% CI 1.01-2.88, 29/1000 more)

15. Kahale LA, et al. Cochrane Database Syst Rev. 2018;6:CD006650.

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DOACs in Cancer-Associated VTE• Hokusai-VTE Cancer – 2018 16

• Edoxaban 60mg daily vs dalteparin for 6-12mo in 1064 patients with CA-VTE

• Discontinuation was at physician discretion at 6mo• Primary outcome: composite of recurrent VTE or

major bleed at 12mo• Edoxaban was non-inferior, but not superior to

dalteparin (12.8% vs 13.5%; HR 0.97 95% CI 0.70-1.36) • Recurrent VTE: Edoxaban not significantly less than

dalteparin (7.9% vs 11.3%; HR 0.71 95% CI 0.48-1.06) • Major bleeding: Edoxaban more than dalteparin (6.9%

vs 4.0%; HR 1.77 95% CI 1.03-3.04, NNH = 35) • Patients spent less time on dalteparin than (184

days vs 211 days, p=0.01), just over half of the patients stayed on treatment for >6mo

• Patient choice / “dosing inconvenience”: 4% vs 14.9%

16. Raskob GE, et al. N Engl J Med. 2018;378:615‐24.

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DOACs in Cancer-Associated VTE• SELECT-D Trial - 2018 17

• Rivaroxaban vs dalteparin for 6mo in CA-VTE in 406 patients• Open label pilot trial, enrollment target of 530 • VTE recurrence at 6mo was 11% for dalteparin and 4% for rivaroxaban (HR 0.43

95% CI 0.19-0.99)• No difference in major bleeds, but clinically relevant bleeding at 6 months was 4%

for dalteparin and 13% for rivaroxaban (HR, 3.76; 95% CI 1.63 to 8.6)• Major bleeds 4x higher in GI cancer on rivaroxaban so enrollment of these cancers was D/C’d

• Upcoming trials• COSIMO – rivaroxaban QOL study• API-CAT: apixaban

17. Young AM, et al. J Clin Oncol. 2018;36:2017‐23.

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Prevention of Cancer-Associated VTE• 2019 ASCO Guidelines14

• Routine pharmacologic thromboprophylaxis should NOT be offered to all outpatients with cancer.

• Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients

• High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or LMWH

• Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting

14. Key NS, et al. J Clin Oncol. 2019;37:JCO1901461.

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Predicting CA-VTEKhorana Score18

• Very High Risk Cancer for VTE (stomach, pancreas) – 2 points

• High Risk Cancer for VTE (lung, lymphoma, gynecologic, bladder, testicular, renal) – 1 point

• Platelets >350k – 1 point

• Hemoglobin <10g/dL or need for epoetin – 1 point

• WBC >11k – 1 point

• BMI >35kg/m2 – 1 point

18. Khorana AA, et al. Blood. 2008;111:4902‐7.

• All items meant to be assessed BEFORE chemotherapy is administered

• Prophylactic pharmacotherapy considered at 2 points

Low Risk 0 points 0.3%

Intermediate Risk 1‐2 points 2%

High Risk 3 points 6.7%

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Prevention of Cancer-Associated VTE

• 2016 Cochrane Review• 26 trials of 12352 ambulatory patients with cancer for primary prophylaxis

• Significant issues with heterogeneity • Attempted to use Khorana score in some comparisons

• LMWH reviewed most extensively • VS Placebo: lower incidence of symptomatic VTE (RR 0.54, 95% CI 0.38-0.75)• VS Aspirin: non-significant decrease in symptomatic VTE in intermediate risk/multiple myeloma

(RR 0.51, 95% CI 0.22-1.17)• VS VKAs: non-significant decrease in symptomatic VTE in high risk/multiple myeloma (RR 0.33,

95% CI 0.14-0.83)

• Only one small study of a DOAC (apixaban) was included with no comparisons

19. Di Nisio M, et al. Cochrane Database Syst Rev. 2016;12:CD008500.

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DOACs in Prevention of Cancer-Associated VTEGuideline-Changing Studies

• AVERT – 2018 20

• Apixaban 2.5mg BID vs placebo for 180 days; 563 patients with Khorona >2 • VTE: Apixaban (4.2%) vs placebo (10.2%) (HR 0.41; 95% CI 0.26-0.65) – NNT 17• Major bleeding: Apixaban (3.5%) vs placebo (1.8%) (HR 2.00; 95% CI 1.01-3.95) -

P=0.046) – NNH 59

• CASSINI – 2019 21

• Rivaroxaban 10mg daily vs placebo; 841 patients with Khorona >2 • Mean intervention period = 4.3mo; 43.7% stopped rivaroxaban early, 50.2% stopped placebo

• VTE was not significantly reduced at 180 days (HR 0.66; 95% CI 0.40-1.09)• “Intervention period” analysis: VTE lower in rivaroxaban (2.3% vs 6.4% - HR0.40; 95% CI 0.20-

0.80 – NNT 25)• Major bleeding was not significantly different (2% vs 1%, p=0.26)

20. Carrier M, et al. N Engl J Med. 2019;380:711‐9.21. Khorana AA, et al. N Engl J Med. 2019;380:720‐8.

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DOACs in Prevention of Cancer-Associated VTE• High risk patients that are NOT good candidates for primary prophylaxis

with apixaban/rivaroxaban• Less than 6mo life expectancy• Brain metastases• Hematologic malignancies (except lymphoma)• ALT >5x UNL• Platelet count <50,000/mm3• Chronic use of antiplatelet or NSAIDs• P-glycoprotein or CYP3A4 inhibitors or inducers• Low body weight (<40kg)• Multiple myeloma with thalidomide/linalidamide treatment

• Probably better treated by LMWH or aspirin

#RxExpo20

Back to the case…

• CC, a 66 year-old-female patient is admitted to your hospital after experiencing a proximal DVT. She has stage III adenocarcinoma of the colon and has recently started FOLFIRI.

• The hospitalist service starts her on dalteparin, but at an excellent CE program you recall learning about a change in treatment recommendations related to CA-VTE.

• Prior to discharge you would:A. Counsel her on administration of dalteparin and continue at least 6moB. Switch to dalteparin to rivaroxabanC. Switch dalteparin to edoxaban after 5 days

Perhaps an option if injections are not an option outpatient… higher major bleed, but better persistence

4x higher bleed risk in GI cancers

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Take Home Points• DOACs may be considered in extended treatment of unprovoked VTE

assuming the patient is not high risk for bleed• Providers should assess the patient’s recurrent thrombosis risk using HERDOO2 or

DASH and include this in consultation with the patient

• Edoxaban and Rivaroxaban may be considered alternatives to LMWH in CA-VTE if the patient is unwilling to do injections and is low risk for bleed

• Apixaban (and maybe Rivaroxaban) may be considered alternatives to LMWH for ambulatory cancer patients with a Khorona score >2

• Benefit is only likely if persistence is encouraged

#RxExpo20

References1. Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet. 2016;388(10063):3060-73.

2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. CHEST. 2016;149(2): 315-52.

3. Nathan AS, Geng Z, Dayoub EJ, et al. Racial, ethnic, and socioeconomic inequities in the prescription of direct oral anticoagulants in patients with venous thromboembolism in the United States. Circ Cardiovasc Qual Outcomes. 2019;12:e005600.

4. Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. Cochrane Database Syst Rev. 2017;12:CD011088.

5. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010; 363:2499-510

6. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med2017;376:1211-22

7. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013; 368:709-18.

8. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 368:699-708.

9. Raskob G, Ageno W, Cohen AT, e al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol. 2016;3:e228-36.

10. Rodger MA, Le Gal G, Anderson DR, et al. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ. 2017;356:j1065.

11. Tosetto A, Testa S, Martinelli I, et al. External validation of the DASH prediction rule: a retrospective cohort study. J Thromb Haemost. 2017;15:1963-70.

12. IBM Micromedex® [Internet database]. Armonk, NY: IBM Truven Health Analytics. Updated periodically.

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References13. Ay C, Beyer-Westendorf J, Pabinger I. Ann Oncol. 2019;30:897–907.14. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with

cancer: ASCO clinical practice guideline update. Clin Oncol. 2019;37:JCO1901461.15. Kahale LA, Hakoum MB, Tsolakian IG, et al. Anticoagulation for the long-term treatment of venous

thromboembolism in people with cancer. Cochrane Database Syst Rev. 2018;6:CD006650.

16. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615-24.

17. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J ClinOncol. 2018;36:2017-23.

18. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-7.

19. Di Nisio M, Porreca E, Candeloro M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2016;12:CD008500.

20. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711-9

21. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380:720-8.

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Chronic Care Management:Focus on Anticoagulation

Tadd Hellwig, Pharm.D., BCPS, FASHP

Professor, South Dakota State University College of Pharmacy and Allied Health Professions

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Disclosure

• Dr. Hellwig reports no actual or potential conflicts of interest associated with this presentation:

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Learning Objectives

• Upon successful completion of this course, participants should be able to:

• Evaluate clinical trials assessing the role of direct oral anticoagulants in patients with stable cardiovascular disease

• Identify the role of direct oral anticoagulants in patients with atrial fibrillation who have undergone a percutaneous coronary intervention

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Patient Case #1• RH is a 58 year-old female in clinic with complaints of lower

extremity pain• Diagnosed with peripheral arterial disease (PAD)

• PMH: • MI in 2018, diabetes, hypertension

• Medications:• Lisinopril 40 mg daily, carvedilol 12.5 mg BID, atorvastatin 40 mg daily,

aspirin 81 mg daily, metformin 1000 mg BID

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Patient Case #1

• What recommendations would you make (if any)?

1. Initiate clopidogrel

2. Initiate clopidogrel and discontinue aspirin

3. Initiate rivaroxaban

4. Initiate rivaroxaban and discontinue aspirin

5. No further adjustments are needed

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Composite endpoint of CV death, MI, stroke

Bhatt DL, et al. JAMA 2010;304(12):1350‐1357

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Bhatt DL, et al. JAMA 2010;304(12):1350‐1357

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• Trial was sponsored by Bayer. The steering committee was comprised of the Population Health Research Institute (study leaders from each country, Bayer representatives) and was responsible for the development of the study protocol. All the data analysis were independently performed at the Population Health Research Institute.

Eikelboom JW, et al. N Engl J Med 2017;377:1319‐30

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Cardiovascular OutcoMes for People Using Anticoagulation StrategieS (COMPASS) trial


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Patient CharacteristicsCharacteristic Rivaroxaban + ASA

(N= 9152)Rivaroxaban(N= 9117)

Aspirin (N= 9126)

Age (yr) 68.3 68.2 68.2

BMI 28.3 28.3 28.4

BP (mmHg) 136/77 136/78 136/78

Cholesterol (mg/dL) 162 162 162

HTN (%) 75.5 75.1 75.4

Diabetes (%) 37.7 37.5 38.1

Previous stroke (%) 3.8 3.8 3.7

Previous MI (%) 61.8 62.0 62.7

ACE‐I/AR (%) 70.7 72.7 70.8

Lipid‐lowering (%) 90.0 90.0 89.4

BB (%) 69.8 70.2 70.1Eikelboom JW, et al. N Engl J Med 2017;377:1319‐30

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Outcome Combination Rivaroxaban ASA Combination vs. ASA Rivaroxaban vs. ASA

N (%) N (%) N (%) HR (95% CI) P‐value HR (95% CI) P‐value

Composite of CV death, stroke, MI

379 (4.1) 448 (4.9) 496 (5.4) 0.76 (0.66‐0.86) <0.001 0.90 (0.79‐1.03) 0.12

Ischemic stroke, MI, ALI, or deathfrom CLD

329 (3.6) 397 (4.4) 450 (4.9) 0.72 (0.63‐0.83) <0.001 0.88 (0.77‐1.01) 0.06

Ischemic stroke, MI, ALI, or CV death

389 (4.3) 453 (5.0) 516 (5.7) 0.74 (0.65‐0.85) <0.001 0.88 (0.77‐0.99)) 0.04

Death from any cause

313 (3.4) 366 (4.0) 378 (4.1) 0.82 (0.71‐0.96) <0.001 0.97 (0.84‐1.12) 0.67

Major bleeding

288 (3.1) 255 (2.8) 170 (1.9) 1.70 (1.40‐2.05) <0.001 1.51 (1.25‐1.84) <0.001

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CAD and PAD subgroups


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COMPASS- Vascular Risk

• Objective: • Identify subsets of patients at higher risk of recurrent vascular events which

may help focus the use of rivaroxaban and aspirin therapy.

• REACH• REduction of Atherothrombosis for Continued Health

• CART• Classification And Regression Trees

• Take home point • ≥2 vascular beds affected, hx of heart failure, renal insufficiency, diabetes

Anand SS, et al. J Am Coll Cardiol 2019;73:3271‐80

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#RxExpo20Anand SS, et al. J Am Coll Cardiol 2019;73:3271‐80

#RxExpo20Anand SS, et al. J Am Coll Cardiol 2019;73:3271‐80

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COMPASS Take Home Points

• Rivaroxaban 2.5 mg BID approved for the prophylaxis of CV event risk in patients with coronary arteriosclerosis and PAD in COMBINATION with aspirin

• Small overall benefit

• Potentially target the higher vascular risk population• >1 vascular bed, heart failure, renal insufficiency, diabetes

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Patient Case #2

• TS is a 62 year old male about to be discharged from the hospital following a MI where a drug-eluting stent was placed

• PMH: hypertension, atrial fibrillation, MI

• Meds: Lisinopril 40 mg daily, carvedilol 12.5 mg BID, atorvastatin 40 mg daily, aspirin 81 mg daily, clopidogrel 75 mg daily

• Apixaban 5 mg BID (currently held)

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Patient Case #2

• What is your preferred treatment in a patient with a recent PCI/stent in addition to atrial fibrillation?

A. DAPT

B. DAPT + DOAC

C. DAPT + warfarin

D. Single P2Y12 inhibitor + DOAC

E. Single P2Y12 inhibitor + warfarin

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PCI AF

https://commons.wikimedia.org/wiki/File:Blausen_0034_Angioplasty_Stent_01.png https://commons.wikimedia.org/wiki/File:Atrial_Fibrillation.png

DAPT > OAC OAC > DAPT

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Stent + Afib

TRIPLE THERAPYDAPT + OAC

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Current Guidelines

• ACS• P2Y12 inhibitor should be given for 1 year post PCI in patients with a

stent

• Antithrombotic therapy for atrial fibrillation• CHA2DS2-VASc (0 in males, 1 in females): reasonable to omit therapy• CHA2DS2-VASc (≥1 in males, ≥2 in females): OAC with DOAC

preferred• Use of antiplatelet (aspirin or aspirin + clopidogrel) is not recommended

Amsterdam E, et al. J Am Coll Cardiol. 2014;64:e139‐228Lip GYH, et al. CHEST. 2018 Epub ahead of print

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Triple therapy

• Dual anti-platelet therapy (DAPT) with concomitant oral anticoagulation (warfarin/DOAC)

• Indications• Atrial fibrillation• ACS and/or PCI with stent placement

• Risks• INCREASED MAJOR BLEEDING

• Numerous trials have demonstrated higher rates

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WOEST Study

• Patients:• Age 18-80, acute PCI, indication for OAC for at least 1 year

• Duration: • 1 year

• Intervention: • Triple: Warfarin + Clopidogrel + Aspirin• Double: Warfarin + Clopidogrel

Dewilde WJM, et al. Lancet 2013;381:1107‐15

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WOEST


44%

19%

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WOEST


18%

11%

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PIONEER AF-PCI Study

• Patients:• Age 18+, just underwent PCI with stent placement, Afib

• Duration:• 1, 6, and 12 months

• Intervention: • Double:

• Rivaroxaban 15 mg once daily + P2y12 inhibitor (Group 1)• Rivaroxaban 2.5 mg twice daily + P2y12 inhibitor (Group 2)

• Triple: Warfarin + DAPT (Group 3)Gibson CM, et al. N Engl J Med 2016;375:2423‐34

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PIONEER

Gibson CM, et al. N Engl J Med 2016;375:2423‐34

27%

18%

17%

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PIONEER

Gibson CM, et al. N Engl J Med 2016;375:2423‐34

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RE-DUAL PCI Study

• Patients:• Age 18+, PCI with stent placement within 120 hours, Afib

• Duration: • 14 months

• Intervention: • Double:

• Dabigatran 110 mg BID + Clopidogrel or Ticagrelor• Dabigatran 150 mg BID + Clopidogrel or Ticagrelor

• Triple: Warfarin + Clopidogrel/Ticagrelor + AspirinCannon CP, et al. N Engl J Med 2017;377:1513‐24.

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REDUAL

Cannon CP, et al. N Engl J Med 2017;377:1513‐24.

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REDUAL

Cannon CP, et al. N Engl J Med 2017;377:1513‐24.

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AUGUSTUS Study

• Patients:• Age 18+, recent ACS or PCI within 14 days, Afib


• Intervention: all patients received a P2y12 inhibitor • Group 1: Warfarin + Aspirin• Group 2: Warfarin + Placebo• Group 3: Apixaban 5 mg BID + Aspirin• Group 4: Apixaban 5 mg BID + Placebo

Lopes RD, et al. N Engl J Med 2019;380:1509‐24

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AUGUSTUS


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AUGUSTUS


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ENTRUST-AF PCI Study

• Patients:• Age 18+, PCI within 5 days, Afib


• Intervention: • Triple: Warfarin + P2y12 inhibitor + Aspirin• Double: Edoxaban 60 mg daily + P2y12 inhibitor

Vranckx P, et al. Lancet 2019;394:1335-43

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ENTRUST


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ENTRUST


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TAKE HOMESTUDY DUAL therapy

Bleeding events(%)

TRIPLE therapyBleeding events(%)

DUAL therapyThrombotic events (%)

TRIPLE therapy Thrombotic events(%)

WOEST(Warfarin)

19.5 44.9 11.1 17.6

PIONEER(Rivaroxaban)

16.8 26.7 6.5 6.0

RE‐DUAL(Dabigatran)

20.2 25.7 13.7 13.4

AUGUSTUS(Apixaban)

9.0 16.1 24.7 26.2

ENTRUST(Edoxaban)

17 20 7 6

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Just when it seemed easy….

• Bleeding risk factors• HAS-BLED score• History of major bleed

• Thrombotic risk factors• Multiple stents• Stent location• History of thrombotic events• Previous stent thrombosis

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Conclusions

• Dual therapy with a DOAC + a single antiplatelet (P2y12inhibitor) in patients with ACS + Afib should be preferred

• Majority of the data is with clopidogrel• DOACs are preferred over warfarin

• Still consider bleeding and thrombotic risk

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DOAC Monitoring Service

Sara Wiedenfeld Pharm.D., BCPS, BCACP

Clinical Assistant Professor University of Iowa College of Pharmacy/Siouxland Medical Education Foundation

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Disclosure

• Sara Wiedenfeld reports no actual or potential conflicts of interest associated with this presentation

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Learning Objectives

• Upon successful completion of this course, participants should be able to:

• Recommend appropriate monitoring parameters for patients on DOAC therapy based on risk stratification.

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DOAC Monitoring

• Safety and efficacy impacted by:

• Renal function• Weight• Age• Drug interactions• Bleeding• Adherence

• Pharmacist role:• Pharmacists are leaders in

anticoagulation monitoring• Increase in DOAC prescribing has

raised question of the pharmacist role in DOAC monitoring

• Medication therapy expert

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Background

• The problem:• Practice site has long standing “anticoagulation clinic”• Patient and provider perceptions• No standard approach• No owner of anticoagulation• Patient tracking is difficult• Peri-procedural management• Financial considerations

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Education

• Standard education developed

• Inclusive of all DOACs

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Start of Therapy

• Collect patient past medical history • Provide patient with patient

education handout • Determine indication for usage

(DVT, PE, stroke, Afib), and duration of therapy

• Switching from warfarin? • First provoked clot 3-6 months • Unprovoked clot 3 months-to

extended • 2nd clot or A Fib extended therapy

• Collect Labs: BMP and calculate CrCl, CBC

• Educate about signs and symptoms of DVT or stroke

• DVT/PE: unilateral pain, numbness, shortness of breath, chest pain

• Stroke: Facial droop, Arm weakness, Slurred speech, Time to call 911

• Financial Analysis • Is the medication covered by patient’s

insurance? • Is there a manufacturer’s coupon

available?

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Follow Up Assessment

• Ask patient if they have any questions or concerns

• Assess adherence: have they missed any doses in the last week

• Are there any bleeding concerns? Ex: excessive bruising, bloody nose, black tarry stools

• Have they started any new medications?

• Ask about refills. Have they refilled their medication? Do they need refills on their medication?

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Follow Up Frequency

Follow-up 6 months (High Risk)

• Appointment in person every 6 months if:

• CrCl <60 ml/min • Age ≥75 y/o

• Assessment questions and repeat creatinine and CBC

Follow-up annually (Low Risk)

• Appointment in person annually for all others:

• Assessment questions• Repeat creatinine and CBC

Initial follow up in 3 months for all patients

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Outcomes

• Goal: Ensure the safe and appropriate use of DOACs for every patient

• Document duration of anticoagulation therapy• Appropriate lab monitoring (CBC and Creatinine)• Documentation of CHA2DS2-VASc score for patients with A Fib

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Outcomes

• DOAC discontinued in over 10% of patients due to exceeding recommended duration

• Aspirin discontinued

• Financial assistance program enrollment

• Patients scheduled for overdue lab tests

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Special Thanks

University of Iowa Pharmacy Students:

Caprisse Honsbruch, Leah Mouw, Zachary Mulford, Jay Tieri

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Take Home Points

• Monitoring is important for all patients taking high risk anticoagulants

• A standard approach to patient monitoring improves patient care

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chronic care management: focus on …...chronic care management: focus on anticoagulation...

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