Outpatient Management of PE - s3.amazonaws.com€¦ · Exam is significant for appearing mildly uncomfortable, ... RCT, randomized clinical ... • 74 yo admitted with GI bleed and

1

Andrew Dunn, MD, MPHProfessor of Medicine

Chief, Division of Hospital MedicineMount Sinai Health System, NY

Outpatient Management of PE

Case-based Discussion of Essential Issues in

Anticoagulant ManagementMarch 8, 2016

DISCLOSURES

Pfizer / BMS Pharmaceuticals – Grant funding

2

PROGRESS!

CASE - PE

A 62 year old man presents to the ED with severe SOB for 6 hours. There is associated right-sided pleuritic chest pain and cough. There is no hemoptysis or dizziness. The patient has a history of htn, DM, and systolic CHF (EF 38%).

Exam is significant for appearing mildly uncomfortable, HR 102, RR 18, BP 148/84. O2 sat (RA) 93%. Chest exam reveals crackles at the right base. The heart exam is normal. There is no edema of either leg.

3

CASE - PE

Labs are significant for WBC 10.1, Hb 13.8. Renal function is normal.

A CTA reveals a PE in a right segmental artery.

The patient lives with his wife. He has Medicare health insurance and has the means to pay for the co-pay for his medications.

CASE - PE

What management strategy would you choose?

A. Admission, start treatment with LMWH + warfarin; discharge after ≥5 days overlap and INR therapeutic

B. Admission, start treatment with DOAC; discharge after ≥5 days

C. Admission, start treatment with DOAC; discharge if status improves in 1-2 days

D. Discharge home from ED on LMWH + warfarin

E. Discharge home from ED on DOAC

4

DOACs vs NOACs

RivaroxabanPE TREATMENT - EINSTEIN

Rivaroxaban 15mg twice daily x 3 weeks then 20mg daily compared with LMWH/warfarin

Open label, noninferiority trial

N = 4,832

EINSTEIN PE Investigators. N Engl J Med .2012;366:1287-97.

5

EINSTEIN PE Investigators. N Engl J Med .2012;366:1287-97.

RECURRENT VTE:2.1% vs 1.8%, p=NS

MAJOR BLEEDING:2.2% vs 1.1%, p=0.003

ApixabanVTE TREATMENT - AMPLIFY

Agnelli G, et al. NEJM. 2013;369:1799-808.

Apixaban 10mg bid x 7 days followed by 5mg BID x 6 months compared with SC LMWH / warfarin

5,244 total patients; 1,836 with PE

Primary endpoint:Recurrent sx VTE or VTE related death

6

AMPLIFYRESULTS

DOACs for the Treatment of VTE

Van der Hulle, et al. J Thromb Haem. 2014;12:320-8.

Meta-analysis comparing DTIs with VKA

Lumpers: DTI (dabigatran) and anti-Xa agents (rivaroxaban, apixaban, edoxaban)

Included: 5 studies (24,455 participants)

7

Van der Hulle, et al. J Thromb Haem. 2014;12:320-8.

EFFICACY OUTCOMES

SAFETY OUTCOMES

Castellucci LA. JAMA. 2014;312(11):1122-1135.

Evidence Network for Recurrent Venous Thromboembolism and Major BleedingThe width of the lines for each connection in the evidence network is proportional to the number of randomized controlled trials comparing each pair of treatments. The size of each treatment node is proportional to the patient-years of follow-up. LMWH indicates low-molecular-weight heparin; RCT, randomized clinical trial; UFH, unfractionated heparin.

Figure Legend:

8

Figure Legend:

For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B) or edoxaban (Grade 2B) over VKA therapy, and suggest VKA therapy over LMWH (Grade 2C).

AT10 - GuidelineVTE Treatment

Kearon C, et al. CHEST Guideline, Chest. 2016.

9

Outpatient PE Treatment

Aujesky D. Lancet. 2011;378:41-8.

Acute PE with low-risk PESI score

Randomized to home vs hospital-based acute care

Received LMWH plus VKA

Primary outcome: Recurrence at 90 days

RCT - 19 hospitals in Europe and US, N = 344


Age +1 per yearMale sex +10Cancer +30CHF +10Chronic lung disease +10Pulse ≥110 +20SBP<100 +30RR ≥30 +20Temperature <36°C +20Altered mental status +60O2 saturation <90% +20

Pulmonary Embolism Severity Index

SCORE<66 I66–85 II86–105 III106–125 IV>125 V

10

Fang MC, et al. JAMA Intern Med. 2015;175:1060-2.

Collaboration of 4 integrated health care delivery systems

5927 patients with acute PE presenting to ED

Anticoagulants - warfarin, LMWH, fondaparinux

PESI Class III or higher: 23%

Outpatient PE TreatmentCardiovascular Research Network Venous

Thromboembolism Study

11

Discharge from ED was uncommon - 8.3%

Discharge from ED increased from 2004 to 2011 (5.6% to 11.1% ).

Most patients did well: Return to ED 18.6% Hospitalized 7.9% Mortality (7 days) 0% Mortality (90 days) 0.4%

Fang MC, et al. JAMA Intern Med. 2015;175:1060-2.

Outpatient PE Treatment - Outcomes

Suitable for outpatient treatment:

1. No contraindications (recent bleeding, severe renal/liver disease, or severe thrombocytopenia)

2. Expected to be compliant with treatment

3. Feels well enough to be treated at home

AT10 - Outpatient PE Treatment

Clinical prediction rules such as PESI (<85 or simplified score 0) can identify low-risk patients

A predefined CPR score is not required Echo and biomarkers not routinely recommended If noted, RV dysfunction or increased biomarker levels should

discourage home treatment

Kearon C, et al. CHEST Guideline, Chest. 2016.

12

Hakemi EU, et al. Chest. 2015;147(3):685-694.

Troponins and PE Prognosis:The Power of the Negative Test

Retrospective study – 298 patients with PE Primary outcomes: Death, CPR, or Thrombolysis Highly sensitive Troponin I used

161 (55%) trop positive 137 (45%) trop negative

Primary Outcome: 0/137 (0%) vs 15/161 (9%), p<0.001

Cho JH, et al. BMC Cardiovascular Disorders. 2014;14:64.

Echocardiogram and PE Prognosis

Meta-analysis - RV dysfunction as a prognostic factor in stable patients with PE

12 trials, 3283 hemodynamically stable patients with acute PE 1223 patients (37.3%) RVD+ 2060 patients (62.7%) RVD-

167/1223 (13.7%)

134/2060 (6.5%)

MORTALITY

13

The Other 50%

Insurance status - DOAC coverage, pre-authorization

Ability to afford co-pay

History of compliance issues

Domiciled

Willing and able - Understand the gravity

Follow-up arranged

Ensure social / logistical issues are fully addressed!

Take Home Points

Use the PESI score to help identify patients who can be treated safely at home - Treat the patient, not the score.

F-Xa inhibitors are as efficacious and safer than LMWH/warfarin.

Troponin and echo are useful tools to help further guide risk stratification when prognosis is uncertain.

Give equal consideration to the other 50%! Ensure all social and logistical aspects are arranged.

14

Direct Oral Anticoagulant (DOAC) Related Bleeding


Anticoagulant Management

Hospital Medicine 2016

San Diego

8 March 2016

Scott Kaatz, DO, MSc, FACP, SFHM

Chief Medical Officer

Hurley Medical Center

Associate Professor of Medicine

Michigan State University

15

• Speaker honorarium– Janssen– Boehringer-Ingelheim– Bristol Myer Squibb/Pfizer– CSL Behring– Daiichi Sankyo

• Consultant– Boehringer Ingelheim– Bristol Myer Squibb/Pfizer– Janssen– Daiichi Sankyo– Portola

• Board membership (non-profit)– Thrombosis and Hemostasis Societies of North America– AC Forum– National Certification Board of Anticoagulation Providers– National Blood Clot Alliance Medical and Scientific

Advisory Board

Full Disclosure

Case

• 74 yo admitted with GI bleed and melena

• AF, CHA2DS2-VASc = 6

• On rivaroxaban (Xarleto), CrCL = 40 ml/min

• Hemoglobin drops 6 hours after admission with mild hypotension

• What would you do in addition to usual support?A. Wait for rivaroxaban to wane, half-life relatively short

B. Give FFP

C. Give PCC

D. Turf to hematology

16

Reversal of DOACs

Camm AJ. Eur Heart J. 2013 Sep;34(36):2850-1. PMID: 23903774.

Anti-Xa Reversal

• PCC human studies

– Only in healthy volunteers

– Improve lab test or punch bx bleeding

• No approved specific reversal agent

– Andexanet in late phase development

Siegal DM. J Thromb Thrombolysis. 2015 Apr;39(3):395-402. PMID: 25586208

17

Systematic Review of Non-Activated PCC Cohort Studies

Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002

Andexanet Alpha

• Short duration of action

• Will require bolus + infusion

• Dose different for apixaban and rivaroxaban

Siegal DM. N Engl J Med. 2015 Dec 17;373(25):2413-24. PMID: 26559317

18

Case

• 74 yo admitted with GI bleed and melena

• AF, CHA2DS2-VASc = 6

• On dabigatran (Pradaxa), CrCL = 40 ml/min

• Hemoglobin drops 6 hours after admission with mild hypotension

• What would you do in addition to usual support?A. Wait for dabigatran to wane, half-life relatively short

B. Give FFP

C. Give PCC

D. Give idarucizumab (Praxbind)

E. Turf to hematology

RE-VERSE AD Study• Question: Can idarucizumab reverse

dabigatran?• Design: cohort study• Patients: 90 who received dabigatran

who needed reversal– 51 with bleeding– 39 with need for invasive

procedure/surgery

• Intervention: Two 50 ml boluses of 2.5 gm dabigatran within 15 min

• Outcome: maximum percentage of reversal of dilute thrombin time and ecarin clotting time at 4 hours

Pollack CV Jr. N Engl J Med. 2015 Aug 6;373(6):511-20. PMID: 26095746

19

RE-VERSE AD Study

• Primary outcome: reversal at 4 hours

– 98% with dilute thrombin time

– 89% with ecarin clotting time

• Median time to cessation of bleeding 11.4 hours


RE-VERSE AD Study

• Thrombotic complications post idarucizumab

– No patient was receiving anticoagulation


Thrombotic eventTime after

idarucizumab

DVT and PE 2 days

DVT 7 daysDVT, PE and left atrial thrombus 9 days

NSTMI 13 days

Ischemic stroke 26 days

20

Protocol to Reverse Dabigatran with Idarucizumab

Eikelboom JW. Circulation. 2015 Dec 22;132(25):2412-22. PMID: 26700008

Ansell JE. N Engl J Med. 2014 Nov 27;371(22):2141-2. PMID: 25371966

Ciraparantag (PER977 or Aripazine)

21

Take Home Points

• Reversing anticoagulation puts the patient at risk for a clot

• Don’t forget to do all of the other things to stop bleeding

• Idarucizumab (Praxbind) is specific for dabigatran (Pradaxa) reversal

• 4 factor inactivated (Kcentra) or activated (FEIBA) PCC should be considered to reverse Anti-Xa drugs

• Restart anticoagulation after reversal when feasible

22

Andrew Dunn, MD, MPHProfessor of Medicine

Chief, Division of Hospital MedicineMount Sinai Health System, NY

Cost-effective Management of PE


Anticoagulant ManagementMarch 8, 2016

CASE - PE

A 58 year-old man with htn and COPD is admitted with SOB for 1 day. He has a dry cough. There is no hemoptysis or chest pain. He was diagnosed with a DVT 4 years ago, for which he received 6 months of warfarin.

His medications are HCTZ, tiotropium MDI and fluticasone MDI.

23

CASE - PE

On exam, the patient appears comfortable. HR 92, RR 16, BP 136/90. O2 sat (RA) 93%. Chest exam is normal. There are no crackles or wheezes and airflow is normal. The heart exam is normal. The right leg is swollen.

Labs are significant for WBC 8.1, Hb 13.0. Renal function is normal. A CTA reveals a PE in a right segmental artery.

The patient lives with his wife. He has commercial health insurance. The hospitalist and PCP discuss the case. The plan is for indefinite anticoagulation.


Age +58Male sex +10Cancer +30CHF +10Chronic lung disease +10Pulse ≥110 +20SBP<100 +30RR ≥30 +20Temperature <36°C +20Altered mental status +60O2 saturation <90% +20

Pulmonary Embolism Severity Index

SCORE<66 I66–85 II86–105 III106–125 IV>125 V

24

CASE - PE

From the perspective of society, the most cost-effective strategy would be:

A. Admission, start treatment with LMWH + warfarin; discharge after ≥5 days overlap and INR therapeutic

B. Admission, start treatment with DOAC; discharge after ≥5 days

C. Discharge home from ED on LMWH + warfarin

D. Discharge home from ED on DOAC

E. Thrombolysis, followed by thrombectomy and IVC filter placement, with lifelong LMWH

Imperative of providing high-value care

Hospitalists as stewards of finite resources

Perspective

Society Payer Hospital Patient

Health Care Costs

25

EINSTEIN PE TrialDischarge with LOS <5 days increased in rivaroxaban group compared with LMWH/VKA (45% vs 33%)

Early Discharge with DOACs

Van Bellen B, et al. Current Medical Research and Opinion. 2014;30:829-37.

Lefebvre P, et al. J Med Econ. 2014;17:52-64.

Markov model - Based on EINSTEIN RCT

Calculated cost, quality-adjusted life-years (QALYs)

Compared to LMWH/VKA

Duration - 3, 6, or 12 months

Probabilities obtained from EINSTEIN trials during treatment and

published literature after treatment

US payer perspective

Cost-effectiveness Analysis

26

Rivaroxaban cost $2,448/patient less and was associated with 0.0058 more QALYs compared with enoxaparin/VKA

Results sensitive to the reduction in LOS associated with rivaroxaban

At a threshold of $50,000/QALY, rivaroxaban is cost-effective compared with enoxaparin/VKA for 76% of cases.

Cost-effectiveness Analysis - Results

Universally truth - Full beds > empty beds

Discharge from ED / Observation Unit

Hospital admission – Low LOS, always

Contribution to Margin – Spinal surgery?

Medication acquisition cost

Rivaroxaban ($18-26/day, BID dosing)

Enoxaparin ($30-120/day) + warfarin (< $1/day)

Readmissions penalty

Cost - The Hospital’s Perspective

27

Health insurance – none, some, plenty Co-pay Duration of Treatment

Cost - The Patient’s Perspective

Take Home Points

Appropriate selection of patients with PE who can be treated primarily at home is a high-value practice

Hospitalists are stewards of limited healthcare resources

Treat the patient, not the disease or score – Address all clinical, social, and logistical concerns

Cost-analyses demonstrate Anti-Xa inhibitors are cost-effective relative to LMWH/warfarin

28

Impact of CKD on Afib Management


Anticoagulant Management

Hospital Medicine 2016

San Diego

8 March 2016

Steve Deitelzweig, MD, MMM, SFHM, FACP

System Chairman – Hospital Medicine

Medical Director – Regional Medical Director

Associate Professor of Medicine – Univ of Queensland

Ochsner Health System

29

• Speaker honorarium– Janssen– Bristol Myer Squibb/Pfizer– Daiichi Sankyo

• Consultant– Bristol Myer Squibb/Pfizer– Janssen– Daiichi Sankyo– Portola

• Board membership (non-profit)– Society of Cardiovascular Patient Care

Disclosure

AF Patients Often Managed by Hospitalists

Study of >55,000 patients aged ≥65 y with AF

• >50% admitted to the hospital for AF within 24 mo – 43.7% for readmissions and comorbidities

• Hypertension (80.5%)• Structural heart disease (32.9%)• Coronary artery disease (23.1%)• Diabetes (19%)

– 60% of patients were receiving warfarin

≈75% of the total direct and indirect costs of AF are hospitalization costs—clinical strategies to optimize care

by improving outcomes are critical58

Deitelzweig S. Ochsner J. 2013;13:2005-419-427.

30

Balancing Stroke and Bleeding Risk: Tools for Assessing Stroke Risk

59

CHADS2 Score1 CHA2DS2-VASc Score*2

Risk Factor Score

Congestive heart failurea 1

Hypertensionb 1

Age ≥75 y 2

Diabetes 1

Stroke/TIA/TE history 2

Vascular diseasec 1

Age 65-74 years 1

Sex category, female 1

MAXIMUM 9

Risk Factor Score

Congestive heart failure 1

Hypertensionb 1

Age ≥75 y 1

Diabetes 1

Stroke or TIA history 2

MAXIMUM 6

1. Gage BF et al. JAMA. 2001;285:2864-2870. 2. Lip GY et al. Chest. 2010;137:263-272. Reproduced with permission of the American College of Chest Physicians. 2. January CT et al. Circulation.2014. Mar 28. pii: S0735-1097(14)01740-9.

*In patients with NVAF, the CHA2DS2-VASc Score is recommended for assessment of stroke risk due to higher sensitivity in patients with CHADS2 Score = 12

Adjusted Risk for Stroke for CHADS2

and CHA2DS2-VASC Scores1,2

Score CHADS2

(%/y)1

CHA2DS2-VASc (%/y)2

0 1.9 0

1 2.8 1.3

2 4 2.2

3 5.9 3.2

4 8.5 4.0

5 12.5 6.7

6 18.2 9.8

7 9.6

8 6.7

9 15.2

1. Gage BF et al. JAMA. 2001;285:2864-2870. 2. Lip GY et al. Chest. 2010;137:263-272.

60

31

Case 4:

White female, age 68 years

AF diagnosed 2 years ago at time of stroke and now admitted with PNA

Hypertension, CHF; CHADS2 = 4

Warfarin initiated poststabilization;

INR frequently out of therapeutic range

Clinical History

Anticoagulation• Warfarin initiated following stroke • Warfarin managed at anticoagulation clinic

– Fran claims: “I take all my pills together, and don’t think about it after that.” Her husband says she sometimes mixes them up

• INR is frequently out of range, requiring regular dose adjustments (estimated TTR = 45%)

Month 2010

32

Clinical History

Anticoagulation (cont)• To investigate the cause of Fran’s fluctuating INR,

the physician asks:– Are you taking any OTC medication?– Have you been treated intermittently with any

antibiotics?– Does your diet/alcohol consumption vary

significantly from week to week?

• answers no to all questions

• inquires about new agent her husband heard about

Current Clinical Assessment

• BP = 122/78 mm Hg; pulse rate = 84 bpm, irregularly irregular

• CBC/SMAC-20 = unremarkable; estimated CrCl = 58 mL/min; HbA1C = 5.6%

• ECG AF rate = 76, indicating left ventricular hypertrophy

• CHADS2 = 4

33

Which Options for Stroke Prevention Would You Endorse?

A. ASA 81 mg po daily and Clopidogrel 75 mg po daily

B. Continue Warfarin with a target INR of 2-3

C. ASA 81 mg po qd

D. DOAC like Dabigatran 150 mg po bid

E. Use another brand for Warfarin like Coumadin

Case Study: Discussion

34

Overview of Phase 3 Clinical Trials in AF: DOACs vs Warfarin

67

1. Connolly SJ et al. N Engl J Med. 2009;361:1139-1151. 2. Connolly SJ et al. N Engl J Med. 2010;363;1875-1876. 3. Patel MR et al. N Engl J Med. 2011;365:883-891.4. Granger CB et al. N Engl J Med. 2011;365:981-992.5. Giugliano RP et al. N Engl J Med. 2013; 369:2093-2104.

RE-LY1,2

N=18,113 (3 arms)ROCKET-AF3

N=14,264ARISTOTLE4

N=18,201ENGAGE AF-TIMI 485

N=14,264

Drug, doseDabigatran

110 or 150 mg BIDRivaroxaban 20 mg QDay

Apixaban 5 mg BID

Edoxaban30 or 60 mg QDay

Adjusted dose?a NoYes: 15 mg QDay if CrCl 30-49 mL/min

Yes: 2.5 mg BID if 2 of: age ≥80 y, weight <60 kg,

SCr ≥1.5 mg/dL

Yes: Both doses halved if: CrCl 30-50 mL/min, weight

≤60 kg, use of verapamil, quinidine, or dronederone

DesignRandomized open-label

Randomized double-blind, double-dummy



Mean age, y 71.5 73 70 72

Prior stroke/TIA/SE

20% 55% 19% 28.5%

Mean CHADS2 2.1 3.5 2.1 2.8

Warfarin naïve 50.4% 37.6% 43% 41%

Comparator Warfarin INR 2-3

64% TTR (mean) 55% TTR (mean) 62% TTR (mean) 65% (mean)

aPatients with the following CrCl (mL/min) excluded: ARISTOTLE: <25 or SCr >2.5 mg/dL; RE-LY: <30; ROCKET-AF: <30; ENGAGE AF-TIMI 48 <30

Dabigatran1 Rivaroxaban2 Apixaban3 Edoxaban4

Drug classDirect factor IIa

inhibitorDirect factor Xa inhibitor

Direct factor Xa inhibitor

Direct factor Xa inhibitor

Time to Cmax 1 h 2-4 h 3-4 h 1-2 h

CYP metabolism NoneCYP3A4/5, CYP2J2, and

hydrolysis are the major means of biotransformation

Mainly by CYP3A4 Minimal

Renal excretion(unchanged drug)

80% of absorbed dose

66% of total dose; 36% of absorbed dose

27% 50%

Protein binding 35% 92-95% 85% 55%

Half-life 12-17 h 5-9 h ≈12 h 9-11 h

Dosing frequency NVAF

BID QDay BID QDay

1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014. 2. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 9/2014. 3. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 4. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; 1/2015.

Pharmacology of DOACs: PK/PD

68

Cmax, time to maximum concentration; PK/PD, pharmacokinetics/pharmacodynamics

35

Drug Dosea

Dabigatran1

• CrCl >30 mL/min, 150 mg orally BID

• CrCl 15-30 mL/min, 75 mg orally BID

• CrCl <15 mL/min or on dialysis, dosing recommendations cannot be provided

Rivaroxaban2

• Take 15 mg and 20 mg tablets with food; take 10 mg tablets with or without food

• CrCl >50 mL/min, 20 mg orally QDay with the evening meal

• CrCl 15-50 mL/min, 15 mg orally QDay with the evening meal

• CrCl <15 mL/min, avoid use since drug exposure is increased

Apixaban3

• 5 mg orally BID• 5 mg orally BID in patients with NVAF and ESRD maintained on hemodialysis• 2.5 mg orally BID in patients with at least 2 of the following characteristics: age ≥80 y, body

weight ≤60 kg or serum Cr ≥1.5 mg/dL

Edoxaban4b• High dose: 60 mg orally QDay• Low dose: 30 mg orally QDay• Both doses halved if CrCl 30-50 mL/min, low body weight ≤60 kg, or taking concomitant verapamil,

quinidine or dronedarone

DOAC Dosing by Indication:Atrial Fibrillation

69

ESRD, end-stage renal disease aPatients with with CrCl < 30 for apixaban and dabigatran and <25 for rivaroxaban excluded from clinical trials . bNot currently approved by the US FDA for this indication1. Pradaxa (dabigatran etexilate mesylate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014.2. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 9/2014. 3. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 4. Giugliano RP et al. N Engl J Med. 2013; 369:2093-2104.

Recommendations COR LOE

Antithrombotic therapy based on shared decision making, discussion of risks of stroke and bleeding and patients preferences

I C

Antithrombotic therapy selection based on risk for thromboembolism I B

CHA2DS2-VASc score recommended to assess stroke risk I B

Warfarin recommended with mechanical heart valves; target INR based on type/location of prosthesis I B

With prior stroke, TIA, or CHA2DS2-VASc score ≥2, OACs recommended; options include:

• Warfarin I A

• Dabigatran, rivaroxaban, or apixaban I B

With warfarin, determine INR at least weekly and monthly when stable I A

Direct thrombin inhibitor or factor Xa inhibitor recommended if unable to maintain therapeutic INR I C

Reevaluate need for anticoagulation at periodic intervals I C

Evaluate renal function prior to initiation of direct thrombin inhibitor or factor Xa inhibitors, and re-evaluate when clinically indicated and at least annually

I B

70

AHA/ACC/HRS Recommendations for Prevention of Thromboembolism in AF

ACC, American College of Cardiology; AHA, American Heart Association; COR, category of recommendation; HRS, Heart Rhythm Society; LOE, level of evidence January CT et al. J Am Coll Cardiol. 2014 ;64(21):e1-e76.

36

Recommendations COR LOE

With nonvalvular AF and CHA2DS2-VASc score of 0, it is reasonable to omit antithrombotic therapy IIa B

With CHA2DS2-VASc score ≥2 and end-stage CKD (CrCl <15 mL/min) or on hemodialysis, it is reasonable to prescribe warfarin for anticoagulation

IIa B

With nonvalvular AF and CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an OAC or aspirin may be considered

IIb C

With moderate to severe CKD and CHA2DS2-VASc score of ≥2, reduced doses of direct thrombin inhibitor or factor Xa inhibitor may be considered

IIb C

For PCI,a bare metal stent may be considered to minimize duration of dual antiplatelet therapy IIb C

Following coronary revascularization in patients with CHA2DS2-VASc score of ≥2, it may be reasonable to use clopidogrel concurrently with OACs, but not with aspirin

IIb B

Direct thrombin, dabigatran, and factor Xa inhibitor, rivaroxaban, are not recommended with AF and end-stage CKD or on hemodialysis b/c of lack of evidence from clinical trials regarding the balance of risks and benefits

III: No benefit

C

Director thrombin inhibitor, dabigatran, should not be used with a mechanical heart valve III:Harm

B

71

AHA/ACC/HRS Recommendations for Prevention of Thromboembolism in AF (continued)

aSee 2011 percutaneous coronary intervention guideline for type of stent and duration of dual antiplatelet therapy recommendationsJanuary CT et al. J Am Coll Cardiol. 2014;64(21):e1-e76.

Conclusions

• Good evolving evidence to support the use of DOACs in Atrial Fibrillation and CKD

• Need to be cautious in those with renal impairment

– Adjust dose or avoid drug altogether when contraindicated

• Transitions of Care: Discharge summary with monitoring recommendations of:

- If CrCl reduced, assess every 3 – 4 months

- If CrCl > 50 ml/min at baseline monitor yearly

37

American College of Cardiology AnticoagEvaluator App

73

An easy, fast way to assess stroke and bleeding risk and the benefits and risks of antithrombotic therapy in patients with chronic AF• Combination risk calculator tool that uses CHADS2, CHA2DS2-VASc, and HAS-BLED

• Enter patient characteristics at the point of care and get individualized annual risk of ischemic stroke and thromboembolism with concurrent annual risk of major bleed

• Compare antithrombotic therapy options based on clinical trials (ACTIVE-A, RE-LY, ROCKET-AF, ARISTOTLE)

Steps for Effective Management of OACs

① Risk assessment to determine if the patient is a candidate for an OAC

② If YES, determine the best agent for each patient based on patient characteristics, preferences, and medication characteristics

Comorbidities/patient population in clinical trial

Pharmacokinetics/pharmacodynamics

Renal function

Dosing/formulation/adherence

Drug-drug interactions

③ Develop a plan for continuity of care

Ensure access

Provide patient education

Ongoing evaluation

741. Heidbuchel H et al. Eur Heart J. 2013;34:2094-2106. 2. Weitz JI et al. American Society of Hematology Education Book. http://asheducationbook.hematologylibrary.org/content/2012/1/536.full. Accessed Sept. 4, 2014.

38

Perioperative Management ofDirect oral Anticoagulants

(DOACs)

Amir K Jaffer, MD, MBA, SFHMProfessor of Medicine

Associate Chief Medical OfficerVice Chair, Patient Safety and QualityDivision Director, Hospital Medicine

Department of Internal Medicine

39

Disclosure Statement

• Consultant– Boehringer-Ingelheim, Janssen

Pharmaceuticals, Pfizer, BMS, Medtronic, Daiichi Sankyo, Astra Zeneca

• Research and Grant Support– NHLBI, Astra-Zeneca

• Board Member– Society of Perioperative Assessment and

Quality Improvement (SPAQI)

Anticoagulation in the Perioperative Period has Become More Challenging

Perioperative

Landscape

Warfarin (Coumadin)

Dabigatran(Pradaxa)

Rivaroxaban(Xarelto)

Apixaban

(Eliquis)

Edoxaban(Savaysa)

• Pharmacokinetics of the NOACs are different

• Lack of Level 1 evidence

• Varying Knowledge about DOACs amongst clinicians

• Litigation

40

Ninth American College of Chest Physicians (ACCP) Recommendations

Risk Stratification

Geerts et al. Chest 2001;119:132S-175S. Douketis et al. Chest 2012;141: e326S-350S

Risk MHV AF VTE

High (>10%/yr risk of TE)

Any MV, older Valve, recent stroke or TIA

CHADS2=5 or 6, recent stroke or TIA or RHD

VTE<3 mths,severe thrombophilia

Moderate (5-10%risk of TE)

Bileaflet AV and one of the following: CHADS

CHADS2=3 or 4 VTE 3-12 mths, recurrent VTE, active cancer

Low (< 5% TE) Bileaflet AV without AF and no other RF

CHADS2=0-2 (No stroke or TIA)

Single VTE> 12 mths

Ninth ACCP RecommendationsPerioperative Management of Patients

Receiving Vitamin K Antagonists

• High Risk for Thromboembolism

– bridging anticoagulation (Grade 2C)

• Moderate Risk for Thromboembolism

– Bridging or no bridging depending on the individual patient or surgery related factors

• Low risk for Thromboembolism,

– No bridging (Grade 2C)

Values and preferences:

Patients who place a higher value on avoiding

perioperative bleeding than on avoiding perioperative thromboembolism are likely to decline heparin bridging

Douketis et al. Chest 2012;141: e326S-350S

41

Managing the patient on Antithrombotic Therapy undergoing an Elective Surgery?

1. Identify the Type of Antithrombotic, dose and indication

2. Patient’s risk factors for thromboembolism (TE) and bleeding

3. Renal Function (CrCl-Cockroft & Gault Formula)

4. Hepatic function

1. Type of Surgery or Procedure

2. Quantify risk of bleeding

3. Quantify risk of thromboembolism

4. Time off antithrombotic therapy

5. Type of Anesthesia

Patient Risk Factors Surgical Risk Factors

Weigh Consequences of Thrombosis, Thromboembolism & Bleeding

(Patient and Provider Preferences)

Establish an Individualized Perioperative Management Plan

Mrs. Z

• 76 yo female with HTN, DM, HF and Atrial Fibrillation is undergoing Laminectomy for severe back pain. The patient’s Creatinine is 1.8. She weighs about 75 kg. She takes Dabigatran 150 mg po BID.

42

The last dose of Dabigatran should be taken when?

1. 5-days before surgery (8-doses)




5. 1-day before surgery (hold only day of surgery doses)

Overview of Pharmacology of DOACs: Impact of PK/PD

Cmax, time to maximum concentration; PK/PD, pharmacokinetics/pharmacodynamics

1. Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 9/2014. 2. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 9/2014. 3. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 4. Camm AJ et al. Drugs. 2011;71:1503-1526. 5. Ogata K et al. J Clin Pharmacol. 2010;50:743-753. 6. Eikelboom JW et al. Circulation. 2010;121:1523-1532. 7. Bathala M et al. Drug Metab Dispos. 2012;40:2250-55.

Dabigatran1 Rivaroxaban2 Apixaban3 Edoxaban4-7

Drug class Direct factor Direct factor Direct factor Direct factorIIa inhibitor Xa inhibitor Xa inhibitor Xa inhibitor

Time to Cmax 1 h 2-4 h 3-4 h 1-2 h

CYP metabolism None CYP3A4/5, CYP2J2, Mainly by 62%and hydrolysis are CYP3A4 fecal elimination

the major means ofbiotransformation

Renal excretion 80% of 66% of total dose; 27% 35% of total(unchanged drug) absorbed dose 36% of absorbed dose; 49% of

dose absorbed dose

Half-life 12-17 h 5-9 h ≈12 h 9-11 h

Dosing frequency BID QD BID QDfor NVAF

43

Preoperative Interruption of DOACs: An Empiric Formulation

Dabigatran Normal or Mild Last dose: Day -3 Last dose: Day -2t1/2 = 14 hrs Impairment before surgery before surgery

(CrCl >50 mL/min) (skip 4 doses) (skip 2 doses)

t1/2 = 15-18 hrs Moderate Impairment Last dose: Day -4 to Last dose: Day -3(CrCl 30-50 mL/min) Day -5 before surgery before surgery

(skip 6-8 doses) (skip 4 doses)

Rivaroxaban Normal or Mild Last dose: Day -3 Last dose: Day -3t1/2 = 9 hrs Impairment before surgery before surgery

(CrCl >50 mL/min) (skip 4 doses) (skip 2 doses)

Apixaban as with rivaroxaban as with rivaroxaban as with rivaroxabant1/2 = 9 hrs

Aim for No or Minimal Aim for Mild-moderateResidual Anticoagulant Residual Anticoagulant

Effect at Surgery (4-5 Drug Effect at Surgery (2-3 DrugHalf-Lives Separate Half Lives Separate

Drug (Half-Life) Renal Function Last Dose & Surgery) Last dose & Surgery)

Douketis. Current Pharmaceutical Design, 2010, Vol 16, No 31

Postoperative Resumption of DOACs: An Empiric Formulation

Dabigatran resume on day after surgery resume 2 days after surgery(24 hrs postoperatively), (48 hrs postoperatively),

150 mg twice-daily 150 mg twice-daily*

Rivaroxaban resume on day after surgery resume 2 days after surgery(24 hrs postoperatively), (48 hrs postoperatively),

10 mg daily 10 mg daily

Apixaban as with rivaroxaban as with rivaroxaban

Douketis. Current Pharmaceutical Design, 2010, Vol 16, No 31

Minor surgery or Procedure Major surgery(low bleeding risk) (high bleeding risk)

*for patients at high risk for thromboembolism, consider administering a reduced dose of dabigatran eg., 110-150 mg once-daily) on evening after surgery and on the first postoperative day.

44

Periprocedural Management of DOACs: Postprocedure Timing of DOAC Resumption

• Depends solely on the postoperative risk for bleeding1,2

– Risk for major bleeding complications postsurgery clearly outweighs risk for thromboembolism1

• For major abdominal or urologic surgery: Delay DOACs until no drainage or signs of active bleeding

• For procedures with good hemostasis shortly afterwards: Resume NOACs a minimum of 4-6 h postsurgery

• In the case of bowel paralysis, bridging with a parenteral anticoagulant may be required

• Dabigatran, rivaroxaban, and apixaban should be resumed 24-48 h after minor procedure, or 48-72 h after major surgery, assuming that hemostasis achieved2

• Dabigatran, Rivaroxaban, Abixaban resume with half-dose for 1-3d depending on surgery, then resume usual maintenance dose1

1. Schulman S et al. Blood. 2012;119:3016-3023. 2. Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1)S2-S11

Do you recommend Bridging with LMWH given a CHADS2

score of 4?

1. Yes

2. No

45

Peri-interventional Management of NOACs: Results from the Dresden Registry

• Evaluation of NOAC management in unselected patients from daily care

• 2179 Patients on NOACs

• 595 underwent 863 procedures, median age 74

• Outcomes adjudicated using standard event definitions

Minimal Procedures were procedures with little tissue traumaMinor procedures were procedures with little tissue trauma but relevant bleeding riskMajor procedures were procedures with relevant tissue trauma and high bleeding risk

Results

CI 0.5-2.0

CI 1.3-11.4

CI 3.3-15.9

CI 0.2-3.4

CI 0.9-5.0

N=863

46

Peri-procedural Management strategies for Anticoagulant Therapy

Vanassche T et al. Eur Heart J 2014;eurheartj.ehu034

Mrs. X

A 78 year-old woman with atrial fibrillation and history of HTN and T2DM on warfarin is scheduled for a total abdominal hysterectomy. Her last INR was 2.2

47

What would you recommend for Perioperative Anticoagulation Management?

1. Stop warfarin 3 days preop and restart 1 day postop

2. Stop warfarin 5 days preop and restart 1 day postop

3. Stop warfarin 5 days preop, bridge with full dose LMWH preop, restart warfarin and full dose LMWH 1 day postop

4. Stop warfarin 5 days preop, admit for IV UFH, restart warfarin and UFH 1 day postop

BRIDGING ANTICOAGULATION IN PATIENTS WHO

REQUIRE TEMPORARY INTERRUPTION OF WARFARIN THERAPY FOR AN ELECTIVE

PROCEDURE OR SURGERY

Thomas L. Ortel, MD, PhD, on behalf of the BRIDGE Investigators and Committees

The BRIDGE trial was funded by the U.S. National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health

48

Hypotheses

We hypothesized that:

1) Forgoing bridging anticoagulation in patients with atrial fibrillation (AF) who needed warfarin held for an operation or invasive procedure would be non-inferior to bridging with LMWH for the prevention of perioperative arterial thromboembolism (ATE)

- and –

2) Forgoing bridging anticoagulation would be superior to bridging with respect to major bleeding

Trial Design

49

Inclusion Criteria• 18 years or older

• Chronic (permanent or paroxysmal) AF or atrial flutter, confirmed by electrocardiography or pacemaker interrogation

• AF associated with valvular disease, including mitral valve disease

• Received warfarin therapy for 3 months or longer, with a target INR therapeutic range of 2.0–3.0

• Undergoing an elective operation or invasive procedure requiring warfarin interruption

• At least one of the following CHADS2

stroke risk factors:

– Congestive heart failure or left ventricular dysfunction

– Hypertension

– 75 years or older

– Diabetes mellitus

– Previous ischemic stroke, systemic embolism, or transient ischemic attack (TIA)

Exclusion Criteria

• Mechanical heart valve

• Stroke, systemic embolism, or TIA within previous 12 weeks

• Major bleeding within previous 6 weeks

• Venous thromboembolism within the previous 12 weeks

• Creatinine clearance <30 mL/min

• Platelet count <100×103 per cubic millimeter

• Planned cardiac, intracranial, or intraspinal surgery

• Unable or unwilling to provide informed consent

50

Primary Outcomes

• Arterial thromboembolism

– Stroke, systemic embolism, or TIA

• Major bleeding

Secondary Outcomes

Acute myocardial infarction, venous thromboembolism, or death

Minor bleeding

Number of patients who

discontinued the study

(n=32)

• Withdrew consent 23• Lost to follow-up 3

• PI decision 2

• Other 4

Number of patients who

discontinued the study

(n=39)

• Withdrew consent 31• Lost to follow-up 3

• PI decision 1

• Other 4

Screen failures (n=4701)

• MD decision 544

• Failed incl/excl 4155

• Reasons not given 2

Number of patients who died

(n=5)

Number of patients who died

(n=4)

Patient Population

Number of patients screened (n=6585)

Number of patients who completed the study (n=913)

Number of patients who completed the study (n=891)

Randomized to placebo (n=950) Randomized to dalteparin (n=934)

Number of patients enrolled (n=1884)

51

Patient Characteristics

Characteristic No Bridging(N=950)

Bridging(N=934)

Age, yr 71.8±8.74 71.6±8.88

Male sex, no. (%) 696 (73.3) 686 (73.4)

Race, no. (%)

White 860 (90.5) 849 (90.9)

Nonwhite 88 (9.3) 82 (8.8)

Unknown 2 (0.2) 3 (0.3)

Weight, kg 96.2±24.87 95.4±23.50

CHADS2 score

Mean 2.3±1.03 2.4±1.07

Distribution, no. (%)

0 1 (0.1) 1 (0.1)

1 216 (22.7) 212 (22.7)

2 382 (40.2) 351 (37.6)

3 229 (24.1) 232 (24.8)

4 96 (10.1) 106 (11.3)

5 23 (2.4) 27 (2.9)

6 3 (0.3) 5 (0.5)

CharacteristicNo Bridging

(N=950)Bridging(N=934)

CHF or left ventricular dysfunction, no. (%)

289 (30.4) 310 (33.2)

Hypertension, no. (%) 833 (87.7) 806 (86.3)

Diabetes mellitus, no. (%) 390 (41.1) 382 (40.9)

Stroke, no. (%) 79 (8.3) 99 (10.6)

TIA, no. (%) 79 (8.3) 77 (8.2)

Mitral valve disease, no. (%)

165 (17.4) 142 (15.2)

Stenosis 19 (2.0) 10 (1.1)

Regurgitation 142 (14.9) 133 (14.2)

Prolapse 13 (1.4) 5 (0.5)

Laboratory values

INR 2.4±0.57 2.4±0.57

Creatinine clearance, mL/min

88.1±39.50 87.6±40.14

Patient Characteristics

52

Surgeries andProcedures*

Surgery/Procedure Type

No Bridging Bridging

Minor, no. (%) (n=781) (n=758)

Gastrointestinal 391 (50.1) 357 (47.1)

Cardiothoracic 139 (17.8) 151 (19.9)

Orthopedic 54 (6.9) 47 (6.2)

Urologic 41 (5.3) 45 (5.9)

Other 156 (19.9) 158 (20.9)

Major, no. (%) (n=94) (n=89)

Orthopedic 29 (30.9) 29 (32.6)

Urologic 26 (27.7) 20 (22.5)

General surgery 16 (17.0) 14 (15.7)

Other 23 (24.5) 26 (29.2)

* Initial classification of surgery/procedure was not always aligned to post-procedure bleeding risk designation

Perioperative Anticoagulant Management

VariableNo Bridging


P Value

Warfarin treatment

Preprocedure time not taking warfarin

Patients with data, no. 872 8390.28

Mean, days 5.2±1.4 5.3±1.8

Time to first postprocedurewarfarin dose


Mean, days 1.5 (1.3) 1.4 (1.0)

Aspirin treatment, no./total no. (%)

Interruption ≥7 days before procedure 92/324 (28.4) 92/329 (28.0)

0.53Interruption <7 days before procedure 41/324 (12.7) 33/329 (10.0)

No interruption 191/324 (59.0) 204/329 (62.0)

53

Perioperative Anticoagulant Management

VariableNo Bridging


P Value

LMWH or placebo

Preprocedure dosePatients with data, no. 796 768

0.61Mean no. of doses 5.0±0.7 5.0±1.4

Patients in whom last dose was taken on the morning of the day before the procedure, no./total no.

778/796 (97.7) 734/768 (95.6) 0.01

Time to first postprocedure dose

Major surgery/procedure (high bleeding risk)


Mean, hr 53.3±31.6 51.3±27.9

Minor surgery/procedure (low bleeding risk)


Mean, hr 21.1±2.3 21.0±2.4

Postprocedure dosesPatients with data, no. 764 721

0.47Mean no. of doses 15.7±7.4 16.1±8.4

Primary Outcomes

OutcomeNo. (%)

No Bridging(N=918)

Bridging(N=895) P Value

ATE 4 (0.4) 3 (0.3)0.01 (non-inf)

0.73 (sup)

Stroke 2 (0.2) 3 (0.3)

TIA 2 (0.2) 0 (0)

Systemic embolism 0 (0) 0 (0)

Major bleeding 12 (1.3) 29 (3.2) 0.005 (sup)

* The mean CHADS2 score in patients who sustained a thromboembolic event was 2.6 (range, 1-4) The median time to an arterial thromboembolic event was 19.0 days (IQR, 6.0-23.0 days)The median time to a major bleeding event after a procedure was 7.0 days (IQR, 4.0-18.0 days)

54

Secondary Outcomes

OutcomeNo. (%)

No Bridging(N=918)

Bridging(N=895) P Value

Death 5 (0.5) 4 (0.4) 0.88 (sup)

Myocardial infarction 7 (0.8) 14 (1.6) 0.10 (sup)

Deep vein thrombosis 0 (0) 1 (0.1) 0.25 (sup)

Pulmonary embolism 0 (0) 1 (0.1) 0.25 (sup)

Minor bleeding 110 (12.0) 187 (20.9) <0.001 (sup)

Limitations

• Few patients had a high CHADS2 score (e.g., 5–6)

• Most patients underwent low-risk procedures, such as colonoscopy or ambulatory surgery

• Overall rate of ATE was lower than initial projections

• Findings should not be applied to patients with mechanical heart valves or venous thromboembolism

• Findings are not applicable to patients with AF treated with a direct oral anticoagulant

55

Conclusions

• For patients with AF who require temporary interruption of warfarin treatment for an elective operation or invasive procedure, a strategy of forgoing bridging anticoagulation was non-inferior to perioperative bridging with LMWH for prevention of arterial thromboembolism

• Forgoing bridging treatment also decreased the risk of major bleeding compared to perioperative bridging with LMWH

Conclusions

• Patients on DOACs require an individualized custom tailored approach during the perioperative period

• Timing of preoperative cessation for DOACs based on elimination half-life

• Patients with Atrial fibrillation and CHADS 2 < 4 are at increased risk of bleeding when using full dose LMWH for bridging

• Discussion of perioperative anticoagulation strategy with patient, anesthesiologist and surgeon is key

56

Questions

Documents

Outpatient Management of PE - s3.amazonaws.com€¦ · Exam is significant for appearing mildly uncomfortable, ... RCT, randomized clinical ... • 74 yo admitted with GI bleed and