BatchelerCari.Outpatient Management of VTE...Burden of VTE •Venous thromboembolism (VTE) affects...

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Outpatient Management of Venous Thromboembolism (VTE)

Cari Batcheler, PharmD, BCPSClinical Pharmacy Specialist – Emergency Medicine

UnityPoint Health – St Luke’s HospitalCedar Rapids, Iowa

[email protected]

Disclosure

• No Conflicts of Interest

Objectives

EvaluateEvaluate primary literature to support outpatient management of VTE

DiscussDiscuss advantages and disadvantages of each direct oral anticoagulant

UtilizeUtilize prognostic models to determine disposition for patients with pulmonary embolism

Describe Describe outpatient treatment regimens for VTE

Topics Covered

Outpatient treatment regimens Disposition

Topics Not Covered

DiagnosisLaboratory tests

Imaging

Inpatient managementThrombolysis

Heparin infusions

Special populationsPregnancy

Cancer

Patient Case• 49 year old male presents with chest pain and shortness of breath

• No significant past medical history

• Family history of factor V Leiden mutation

• BP 132/80 mmHg

• Pulse 80 beats per minute

• Temp 36.4 OC

• RR 18

• SpO2 97% on room air

• CBC and within normal limits except serum creatinine = 1.18 mg/dL

• Troponin <0.02 ng/mL

• CTA of chest showed bilateral pulmonary emboli with no evidence of right ventricular dysfunction

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Burden of VTE

• Venous thromboembolism (VTE) affects 900,000 people each year• Includes deep vein thrombosis (DVT) and pulmonary

embolism (PE)• 100,000 die of PE annually• Mortality rates of PE with shock exceed 30%

• 30-day morality rate of low-risk PE is less than 1%

Beckman MG, et al. Am J Prev Med. 2010;38(4 Suppl):S495-501.Kasper W, et al. J Am Coll Cardiol. 1997;30(5):1165-71.Beam DM, et al. Acad Emerg Med. 2015;22(7):788-95.

Phases of VTE Treatment

Initial Phase• First 7 days

Long Term Phase• 7 days to 3 months

Extended Phase• Beyond 3 months

Kearon C, et al. Chest. 2016;149(2):315-352.

Choice of Therapy

In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant

therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy.


Advantages of Direct Oral Anticoagulants (DOACs)

Predictable pharmacokinetics

and pharmacodynamics

Few drug and food interactions

No dietary restrictions

Rapid onset and offset

Short half-life Less laboratory monitoring

Wide therapeutic window

No need for parenteral

anticoagulation*

Mekaj YH, et al. Ther Clin Risk Manag. 2015;11:967-77.

Disadvantages of DOACs

No standardized test for monitoring

Rapid offset and short half-life

Antidotes costly and not widely available

High cost

More difficult to monitor compliance

Mekaj YH, et al. Ther Clin Risk Manag. 2015;11:967-77.

DOAC Dosing for VTE Treatment

Drug Dose Trial

Apixaban 10mg twice daily for 7 days, then 5mg twice daily AMPLIFYa

Dabigatran Parenteral anticoagulation for 5-10 days, then 150mg twice daily RE-COVERb,c

Edoxaban Parenteral anticoagulation for 5-10 days, then 60mg once daily Hokusai-VTEd

Rivaroxaban 15mg twice daily for 3 weeks (21 days), then 20mg once daily EINSTEINe,f

a. Agnelli G, et al. N Engl J Med. 2013;369:799-808; b. Schulman S, et al. N Engl J Med. 2009;361:2342-2352; c. Schulman S, et al. Circulation.2014;129:764-772; d. Hokusai-VTE Investigators. N Engl J Med. 2013;369:1406-1415; e. EINSTEIN Investigators. N Engl J Med. 2010;363:2499-510; f. EINSTEIN–PE Investigators. N Engl J Med. 2012;366:1287-1297.

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Choice of AnticoagulantFactor Preferred Agent(s) Agent(s) to AvoidParenteral therapy to be avoided

Rivaroxaban, apixaban Dabigatran, edoxaban, VKA

Once daily oral therapy preferred

Rivaroxaban, edoxaban, VKA Apixaban, dabigatran

Liver disease and coagulopathy LMWH DOACs, VKA

Renal disease and creatinine clearance <30 mL/min

VKA, apixaban*Dabigatran, edoxaban, rivaroxaban

Coronary artery disease VKA, rivaroxaban, apixaban, edoxaban

Dabigatran

Dyspepsia or history of GI bleeding

VKA, apixaban Dabigatran

Poor compliance VKA Dabigatran


DOAC Elimination

Galgani A, et al. Front Neurol. 2018;9:1067.

DOAC Drug Interactions

Dalal J, et al. Indian Heart J. 2015;67 Suppl 2:S13-34.

Extended Treatment of VTE

Drug Dose TrialApixaban 2.5mg BID AMPLIFY-EXTa

Dabigatran 150mg BID RE-MEDY & RE-SONATEb

Edoxaban 60mg daily Hokausi-VTEc

Rivaroxaban 10mg daily EINSTEIN-EXTd

a. Agnelli G, et al. N Engl J Med. 2013;368:699-708.b. Schulman S, et al. N Engl J Med. 2013;368:709-718.c. Raskob G, et al. Lancet Haematol. 2016;3(5):e228-36.d. EINSTEIN Investigators, et al. N Engl J Med. 2010;363:2499-2510.

DOAC Monitoring

Baseline CMP, CBC, and coagulation

studies

Repeat at least annually

Routine coagulation testing not required

Disposition

In patients with low-risk PE and whose home

circumstances are adequate, we suggest treatment at home or early discharge over standard discharge

(e.g., after the first 5 days of treatment).


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Rates of Discharge Home

• Outpatient treatment for DVT is the standard of care

• Prevalence of discharge home for PE patients is low• 1 to 8%

Vinson DR, et al. Ann Intern Med. 2018;169(12):855-865.

Home Treatment of

PE

983 emergency department patients with

pulmonary embolism

746 patients potentially eligible for outpatient

treatment

13 patients (1.7%) treated at home

733 patients (98.3%) admitted to the hospital

237 considered ineligible for

outpatient treatment

Stein PD, et al. Am J Med. 2016;129(9):974-7.

Benefits of Outpatient Treatment

Cost savings

Patient preference

Conservation of resources

Avoid risks associated with inpatient care


Risks of Hospitalization

Patients with low-risk PE who were admitted to the hospital were 8 times more likely to develop a hospital acquired condition• 13.3% vs 1.5% (95% CI: 3.77-19.94)

Bacterial pneumonias were also more common in hospitalized patients

• 11.7% vs 5.9% (95% CI: 1.24-3.23)

Among long LOS patients, hospital acquired conditions (52) exceeded adverse PE events (14 recurrent DVT, 5 bleeds)

Wang L, et al. PLoS ONE. 2017;12(10):e0185022.

Criteria for Outpatient Treatment of PE

Clinically stable with good

cardiopulmonary reserve

No contraindications

to anticoagulation

Recent bleeding

Severe renal or liver disease

Severe thrombocytopenia

(i.e. <70,000/mm3)

Expected to be compliant with treatment

Feels well enough to be treated at home


Contraindications to Outpatient Treatment

Right ventricular dysfunction

Elevated troponin Hemodynamically unstable

Oxygen requirement


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Timeline

PESI Score developed

2005

Hestia Criteria developed

2011

PESI Score validated for outpatient use

2011

Rivaroxaban approved for treatment of VTE

2012

Apixaban and dabigatran approved for treatment of VTE

2014

Edoxaban approved for treatment of VTE

2015

Beam, et al.

2015

Roy, et al.

2017

Mercury PE and eSPEED

2018

HoT-PE

2019

Hestia Study

• First published by Zondag and colleagues in 2011• Objective: to evaluate the efficacy and safety of

outpatient treatment of selected patients with acute pulmonary embolism• Prospective cohort study included 297 patients with PE• Enrolled subjects from May 2008 to April 2010• Treated with LMWH and VKA• Discharged immediately from the ED or admitted for less

than 24 hours (23%)

Zondag W, et al. J Thromb Haemost. 2011;9(8):1500-7.

Adapted Hestia Criteria

• Hemodynamically unstable by clinician judgement• Thrombolysis or embolectomy needed• Active bleeding or high risk for

bleeding• GI bleeding or surgery ≤2 weeks ago• Stroke ≤1 month ago• Bleeding disorder or platelet count

<75,000/mm3

• Uncontrolled hypertension (SBP >180 or DBP >110)

• Oxygen needed to maintain SaO2 >90%• PE diagnosed while on anticoagulation• Requiring IV pain medication• Medical or social reason for admission• Creatinine clearance <30 mL/min• Severe liver impairment• Known history of heparin induced

thrombocytopenia• Pregnant


Hestia Study Results

• 2% of patients had recurrent VTE during the 3

month follow-up period

• 95% CI: 0.8 – 4.3%

• No fatal VTE events

• 0.7% of patients had a major bleeding episodes

• 95% CI: 0.08 – 2.4%

• One fatal intracranial bleed

• 5.1% of patients had clinically relevant non-

major bleeding

• 95% CI: 2.9 – 8.2%


Hestia Study Conclusion

Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis

Subsequently validated by multiple studies


Patient Case• 49 year old male presents with chest pain and shortness of breath

• No significant past medical history

• Family history of factor V Leiden mutation

• BP 132/80 mmHg

• Pulse 80 beats per minute

• Temp 36.4 OC

• RR 18

• SpO2 97% on room air

• CBC and CMP within normal limits except serum creatinine = 1.18 mg/dL

• Troponin <0.02 ng/mL

• CTA of chest showed bilateral pulmonary emboli with no evidence of right ventricular dysfunction

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Patient Case

Is this patient a candidate for outpatient treatment?

Yes 0% mortality in 90 days

2% incidence of VTE recurrence

Is this patient considered low risk based on the Hestia Criteria?

Yes

Pulmonary Embolism Severity Index (PESI)• Originally published by Aujesky and colleagues in 2005 • Retrospective cohort study from 2000 to 2002• Inpatients >18 years old • Primary or secondary diagnosis of PE

• 15,531 patients from 186 hospitals were identified• 10,354 (67%) randomly selected for derivation• 5,177 (33%) for internal validation

• Logistic regression analysis used to identify 11 criteria that were associated with 30-day mortality

Aujesky D, et al. Am J Respir Crit Care Med. 2005;172(8):1041-6.

PESI CriteriaPredictors Points AssignedAge 1 point per yearMale sex 10Cancer 30Heart failure 10Chronic lung disease 10Pulse ≥ 100 beats/min 20Systolic blood pressure <100 mmHg 30Respiratory rate >30/min 20Temperature <36 C 20Altered mental status 60Arterial oxygen saturation <90% 20


PESI Score Interpretation

PESI Score Class 30 day Mortality Risk0-65 I (very low risk) 0.0-1.6%

76-85 II (low risk) 1.7-3.5%

86-105 III (intermediate risk) 3.2-7.1%

106-125 IV (high risk) 4.0-11.4%

≥125 V (very high risk) 10-24.5%


Patient Case

• 59 • 1 point per year (49) + 10 points for male sex

What is the patient’s PESI score?

• Very low risk (Class I)• 0 – 1.6% risk of 30-day mortality

To which class does this score correspond?

PESI Outpatient Validation

Study

• Open-label non-inferiority trial in 19 EDs in Switzerland, France, Belgium, and USA

• Included patients between 2007 and 2010 who • Had been diagnosed with symptomatic PE• Low risk PESI scores (Class I or II)

• Excluded those in shock, hypoxia, or bleeding risk• 334 patients randomized in 1:1 ratio to inpatient or

outpatient treatment• 171 were treated as outpatients• 168 were treated as inpatients

• Everyone got subcutaneous LMWH followed by oral anticoagulation

Aujesky D, et al. Lancet. 2011;378(9785):41-8.

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PESI Outpatient Validation Study

Demonstrated non-inferiority of outpatient management for recurrent PE and death• 1 patient (0.6%) in each group died within 90 days• 1 (0.6%) outpatient and 0 inpatients had a recurrent PE

Outpatient management also non-inferior to inpatient management for major bleeding up to 14 days

Narrowly missed non-inferiority margin for outpatient management for bleeding to 90 days• 3 (1.8%) outpatients and 0 inpatients had major

bleeding events in 90 days

Aujesky D, et al. Lancet. 2011;378(9785):41-8.

Beam, et al.

Prospective observational study

Two academic emergency departments

Utilized modified Hestia criteria to identify

low risk PE patients

106 patients with VTE

discharged on

rivaroxaban

71 (67%) with DVT

30 (28%) with PE

5 (5%) with DVT and PE

Beam DM, et al. Acad Emerg Med. 2015;22(7):788-95.

Beam, et al.

Patients were followed for a mean of 389 days

No patient developed a recurrent or new VTE

while on therapy

3 patients had VTE recurrence after

completing their prescribed courses of

anticoagulation

No patients had a major bleeding event


Beam, et al. Limitations

Observational study Small sample size

No control group Duration of anticoagulation not

disclosed


Beam, et al. Conclusions

Low-risk ED patients with deep vein thrombosis and pulmonary

embolism can be treated at home with a low rate of venous thromboembolism recurrence

and low rate of bleeding.


Roy, et al.

• Retrospective propensity-score matched cohort study• Patients diagnosed with a symptomatic

acute PE between January 2007 and December 2012• Exclusion criteria:

• Age ≤ 18 years• PE diagnosed during hospitalization• Chronic PE• Cardiogenic shock at admission• Thrombolysis, surgery, radiovascular

intervention, or IVC filter placement• No anticoagulation treatment • Follow-up for PE outside the Ottawa Hospital

Roy PM, et al. J Thromb Haemost. 2017;15(4):685-694.

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Roy, et al.

Patients selected for outpatient treatment were

discharged home from the ED and seen within 24 hours

of the diagnosis at a dedicated thrombosis clinic

Follow up at 7–14 days and 90 days

Outpatients defined as those discharged directly from

the emergency room and patients discharged within 48

hours of admission

Outpatients matched to inpatients using propensity

scores

Primary outcome: combination of major bleeding,

recurrent VTE, or all-cause death within 14 days of the

diagnosis of PE


Roy, et al. Results

• 583 (51.7%) required hospitalization• 544 (48.3%) were managed as

outpatients• 485 discharged from the emergency

department and 59 discharged within 48 hours

1127 patients included

• Confusion (n = 6)• Nosocomial infection (n = 6)• Falls (n = 2)• Several events (n = 5) • Miscellaneous (n = 9)

During hospitalization,

28 patients (2.5%) had a

serious iatrogenic

event


Roy, et al. Results

Inpatients Outpatients P valueCombined events (14 days) 13.0% 3.3% 0.011

Recurrent VTE 1.7% 0.6% 0.135Recurrent VTE + PE related death 9.2% 2.0% 0.026Major bleeding 3.8% 0.0 <0.001All cause mortality 8.2% 2.8% 0.104

Combined events (3 months) 21.7% 6.9% 0.001Recurrent VTE 4.7% 3.6% 0.586Recurrent VTE + PE related death 15.7% 4.8% 0.004Major bleeding 5.9% 0.7% <0.001All cause mortality 16.3% 3.2% 0.005


Roy, et al. Conclusions

Hospitalized normotensive patients with acute PE

have a higher risk of recurrent VTE, major bleeding,

or death than patients managed as outpatients

None of the outpatients with a low PESI risk (PESI

class I/II) had recurrence of VTE, major bleeding, or

death during the first 2 weeks after the diagnosis

• 5.1% for hospitalized patients and 0% for outpatients

• P = 0.005

Low-risk patients can be safely managed as

outpatients


Mercury PE Study

Randomized, open-label, parallel group, multicenter study

Adult patients presenting to the emergency department with objectively confirmed low risk PE

Low risk PE defined by the absence of any Hestia criteria

Exclusion criteria:Elevated troponinContraindications to anticoagulationBarriers to follow-up

Mercury PE

114 patients randomized in 1:1 ratio to ED discharge on rivaroxaban or standard care

Principal investigators and outcome adjudicators were masked to group assignment

Primary efficacy outcome: time spent in the hospital in the 30 day period after randomization

Primary safety outcome: major bleeding within 90 days

Peacock FW, et al. Acad Emerg Med. 2018;25(9):995-1003.

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Mercury PE Results

• Mean duration of initial and subsequent hospitalizations for bleeding and/or VTE events within 30 days of randomization was shorter in the rivaroxaban group versus standard of care• 4.8 hours vs 33.6 hours (p<0.0001)• Mean difference in length of stay was 28.8 hours

(95% CI: -41.5 to -16.2)

• No recurrence of VTE or VTE related death within 90 days of randomization for either group

• No differences in bleeding-related hospitalizations or physician visits within 90 days of randomization for rivaroxaban vs standard of care• 3.9% vs 6.3%


Mercury PE Conclusions

and Limitations

Early discharge on rivaroxaban was associated with a

significant cost savings (~$2,500) compared to standard

care

Standard of care migrated to early discharge on

rivaroxaban throughout the study period

Underpowered to detect differences in safety outcomes

ED admission for a limited period of intravenous

anticoagulation provides little benefit over immediate

ED discharge


Electronic Support for Pulmonary Embolism Emergency Disposition(eSPEED) Trial

Controlled pragmatic trial from January 2014 to

April 2015

21 emergency departments in Kaiser Permanente system in

Northern California

Included patients 18 years or older with acute

PE

Utilized a clinical decision support system (CDSS) to

assist with disposition decision making

PESI score utilized to guide clinicians


eSPEED

1703 patients were included

• 46.9% directly from the ED• 53.1% after a brief observation period (<24 hours)

324 patients were discharged home

• 31.8% versus 21.1% (p = 0.016)

Activation of the CDSS was associated with increased home discharge

• 27.7% to 41.1%

Home discharge increased from pre- to postintervention for low-risk PE

• 12% to 6.2%

Rates of PE-related return visits within 5 days decreased from pre- to postintervention


eSPEED Conclusions

Implementation and promotion of an EHR-integrated CDSS safely reduced hospitalization

of ED patients with acute PE

For every 100 ED patients with acute PE, 11 hospitalizations were avoided

Estimated cost reduction of $80,000 per 100 patients


HoT-PE

• Prospective multicenter single-arm trial

• Patients with acute low-risk PE without

• Hemodynamic instability

• Right ventricular dysfunction or intracardiac thrombi

• Serious comorbidities

• Utilized adapted Hestia Criteria to exclude patients

• Patients could be admitted for up to 48 hours

• Primary outcome: symptomatic recurrent VTE or PE-

related death within 3 months of enrolment

Barco S, et al. Eur Heart J. 2019;

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HoT-PE Results

• Study terminated for efficacy after the predefined interim

analysis

• 525 patients included in the pre-planned interim analysis

• Primary efficacy outcome occurred in three patients (0.6%)

• One-sided upper 99.6% CI 2.1%

• One-sided P-value <0.0001

• All three recurrent events presented as non-fatal PE

• 6 of 519 patients (1.2%) in the safety population had a

major bleeding episode

• Two-sided 95% CI 0.4–2.5%

Barco S, et al. Eur Heart J. 2019;

Evidence Summaries• 13 Meta-analysis by Zondag, et al.a

• Included observational studies• 13 studies (1657 patients) with outpatients (discharged <24 hours)• 3 studies (256 patients) with early discharge patients (discharged

within 72 hours) • 5 studies (383 patients) with inpatients

• Incidences of recurrent VTE, major bleeding, and mortality were comparable between the three groups

• Home treatment or early discharge of selected low-risk patients with pulmonary embolism is as safe as inpatient treatment

• 2018 Cochrane Reviewb

• Included 2 randomized control trials (Aujesky 2011 and Mercury PE)

• No evidence of any clear difference between the interventions in overall mortality, bleeding, and recurrence of PE

a. Zondag W, et al. Eur Respir J. 2013;42(1):134-44. b. Yoo HH, et al. Cochrane Database Syst Rev. 2019;3:CD010019.

Cost Savings

If all eligible patients with PE seen in U.S. emergency

departments were treated at home rather than in the

hospital, health care costs would decrease by $1 billion

per year.

Dalen JE, et al. Am J Med. 2016;129:899-900.

Patient Case

• Yes• No contraindications to outpatient

management per Hestia Criteria• Very low risk according to PESI score

Can this patient be safely managed as an

outpatient?

• Apixaban 10mg BID for 7 days, then 5mg BID

• Rivaroxaban 15mg BID for 21 days, then 20mg daily

If the patient prefers not to be treated with parenteral

anticoagulants, which regimens would be

acceptable?

Patient Education

Risks of outpatient treatment

Close return precautions

Signs and symptoms of recurrent VTE

Signs and symptoms of bleeding

Importance of adherence

Avoid NSAIDs

Fall precautions

Alcohol in moderation

Summary

DOACs have revolutionized the management of VTE

Utilize validated prognostic models to risk-stratify patients with PE

Low-risk patients with PE can be safely treated at home

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[email protected]

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