Anticoagulation in Clinical Medicine 2018

Disclosures Funding from National Institutes of Health, Department of Veterans Affairs, American Heart Association

Education Need/ Practice Gap: A major practice gap exists in the indications for use of anticoagulants. There is a small window for therapeutic dose adjustment. Close monitoring of the patients and anticoagulant medications are needed to provide a reduction in thrombosis with the lowest occurrence of bleeding.

Objectives • Describe management considerations for the use of anticoagulant medications • Describe best practices for the management of venous thromboembolic disease • Describe the best practices for preventing stroke in atrial fibrillation

Expected Outcome The desired change/result in practice is to optimize the benefits and minimize the risks in the use of anticoagulant medications.

PollEverywhere

TEXT 37607 ENTER SUSANSMYTH180

Global Burden of Thrombosis

1 in 4 deaths is caused by arterial or venous thrombosis

Oral Anticoagulants and their Effects on Coagulation Cascade

Warfarin

Rivaroxaban Apixaban Edoxaban Betrixaban

Dabigatran

What to call the non-vitamin K antagonists ?

NOAC = non-vitamin K antagonist/warfarin oral anticoagulant DOAC = direct acting oral anticoagulant

Cardiologist wrote NOAC, meaning “nonwarfarin anticoagulant” This was misinterpreted as “no anticoagulant” and patient’s warfarin was discontinued.

Optimize Benefits, Minimize Risk

Bleeding Thrombosis

An ideal anticoagulant will provide the greatest reduction in thromboembolism with the lowest incidence of bleeding.

• Identify “red flags” • Control modifiable risk factors

• Assess thrombosis risk • Control modifiable risk factors

Choose an evidence-based anticoagulant regimen • Appropriate dosage adjustment • Identify drug-drug interactions • Provide education • Provide ongoing monitoring and adherence

Burden of Venous Thromboembolic Disease

Increases with age Prevalence and Projections 2002 - 2050

Burden of Venous Thromboembolic Disease

PE is the most preventable cause of death in hospitalized patients

Pathophysiology of VTE

Endothelial cell activation Release of VWF,

P-selectin expression

NET formation RBC accumulation

fibrin formation

Thrombolysis

mediated by plasmin, ADAMTS13, DNase

Platelet and neutrophil adhesion

Therapeutic Management of PE Depends on Classification

Low Risk PE

• Normal BP • Normal RV

function

Submassive Massive PE 1 – 5% cases 70 – 75% cases 20 – 25% cases

• Normal BP • Evidence for

right ventricular dysfunction

• Hypotension • Need for

vaspressors • Cardiac arrest

Additional risk factors associated with worse outcomes – PESI score

PESI Simplified Age> 80 Male History of Cancer History of Heart Failure History of Chronic Lung Disease Pulse ≥ 110/min Systolic BP <100 mmHg Respiratory Rate ≥ 30/min Temperature < 36° C / 96.8° F Altered Mental Status Arterial oxygen saturation < 90%

Age > 80 Cancer Cardiopulm. dz. Pulse ≥ 110/min SBP <100 mmHg oxygen sat < 90%

Case 1 Case : 32yo female in ED after skiing accident 1 week ago presenting with swollen RLE and SOA and found to have RLE DVT and segmental PE by CT/PE scan. She has no other conditions but takes oral contraceptives. Hemodynamically stable and normotensive Normal cardiac troponin level. RV/LV ratio on CT/PE scan <0.9 (normal) She is given LMWH in ED.

Case 1

Case 1: What would you recommend for oral anticoagulation? A. LMWH bridge to warfarin B. Stop LMWH, start rivaroxaban C. LMWH at least 5 days then switch to dabigatran D. Stop LMWH, start apixaban E. Any of the above

Pharmacologic Intervention

Give first dose as soon as possible

Already received therapeutic enoxaparin within last 8 hours (e.g., outside hospital)

Known or suspected active major bleeding

Confirmed history of heparin induced thrombocytopenia (HIT) or thrombocytopenia and suspected HIT

Spinal anesthesia or lumbar puncture

Hypersensitive to enoxaparin or heparin products

Low Molecular Weight Heparin (1 mg/kg up to 150 mg)

Clinical Trials of DOAC in VTE: Recurrence

DOAC vs Warfarin for Acute VTE – Real World Efficacy

Outcome RR Lower Limit

Upper Limit

Recurrent VTE 0.88 0.74 1.05

Fatal PE 1.02 0.39 5.96

Overall Mortality 0.97 0.83 1.14

0.1 1 10 Favors DOACs Favors VKAs

Data drawn from a meta-analysis comparing all 4 approved DOACs with warfarin; DOACs non-inferior to LMWH, VKA for efficacy2

Clinical Trials of DOAC in VTE: Bleeding

DOAC vs Warfarin for Acute VTE – Real World Safety

Outcome RR Lower Limit

Upper Limit

Major bleeding 0.60 0.41 0.88

Non-fatal bleeding at critical site 0.38 0.23 0.62

Clinically relevant non-major bleeding 0.76 0.58 0.99

Non-fatal intracranial bleeding

0.39 0.16 0.94

Major GI bleeding 0.68 0.36 1.30

Fatal bleeding 0.36 0.15 0.87

0.1 1 10 Favors DOACs VKAs

40% reduction in major bleeding

Special Populations with VTE Elderly: GREATER reduction of recurrent VTE in patients >75 years LOWER major bleeding lower with DOAC (1.8% vs 4.7% with warfarin) Renal Failure GFR 30 – 50 ml/min: LOWER recurrent VTE LOWER bleeding In patients randomized to DOAC versus warfarin Obesity: Similar relative risk reduction in patients who weighed ≥ 100kg versus < 100 kg)

American Associations of Chest Physicians

Recommend DOAC over warfarin for initial and long term treatment of VTE in patients without cancer.

Populations that are not suitable for DOAC Severe renal or hepatic insufficiency Initial high risk of bleeding – this is one place where UFH would be preferred initially, and then can transition to DOAC once bleeding risk is lower Unable to afford

Outpatient Management of Low Risk PE

LMWH x 1 dose

prescribe DOAC D/C Home

PESI score 1 – 2 Hemodynamically stable (HR <110, BP >100) No major medical issues Early follow-up available

Requiring oxygen Co-morbid conditions Non-compliant / adherent to treatment plan Other psychosocial barriers to outpatient treatment

Management of Submassive and Massive PE UK OptimalCare® Protocol for PE

Hemodynamically stable: • Initiate anticoagulation with

enoxaparin 1mg/kg SQ X 1 dose if no contraindication (Table 1)

• Order troponin T and EKG • Is RV/LV ratio ≥1 or troponin T >0.1?

Patient in shock?

Systolic SBP < 90 and/or use of

vasopressors, cardiac arrest, or bradycardia

*MASSIVE PE* 30-day mortality (>15%) 1

• Call UKMDs and Activate “PERT” • Initiate anticoagulation with heparin

IV bolus (80 units/kg to max. 8000 units) if no contraindication (Table 1)

• PERT: Is patient a candidate for ECMO?

• Consider systemic thrombolysis (tPA) if no contraindications

• ECMO and definitive therapy

*LOW RISK PE* 30-day mortality (≤1%) 1

Anticoagulation alone:

• Direct oral anticoagulants (apixaban or rivaroxaban)

or • Enoxaparin + warfarin or • Heparin drip + warfarin

YES

YES

YES

NO

NO

NO

*SUBMASSIVE PE* 30-day mortality (3-15%) 1

Call UKMDs and Activate “PERT” to assist with risk stratification / advanced therapy options:

• INTERMEDIATE / LOW RISK: RV dysfunction or troponin T >0.1 Anticoagulation alone and close observation

• INTERMEDIATE / HIGH RISK: HR >110; RV dysfunction troponin T >0.1

Catheter-directed thrombolysis (CDT) if no contraindications or Consider embolectomy if CDT contraindicated

1Simplified PESI risk factors to predict 30-day mortality: • age >80; • cancer; • chronic cardiopulmonary disease; • HR>110; • SBP <100; • O2 sat <90%

VTE Prevention

The PERT consortium brings together clinicians who focus on pulmonary embolism to better the treatment of these patients

VTE Prevention – Extended Therapy APEX trial: Evaluated n=7,513 patients treated with betrixaban for a median 36 days or enoxaparin 40mg SQ once daily for median 9 days in patients hospitalized for acute medical illness who were at risk for thromboembolic complications due to moderate or severe restricted mobility

40 75

Symptomatic VTE

Pro

babi

lity

of S

ympt

omat

ic E

vent

(%)

Time (Days)

Enoxaparin

Betrixaban

1.44%

0.93%

Through Visit 3 HR = 0.65 (0.42, 0.99) ARR = 0.51% NNT = 196

p=0.043

Through End of Trial* HR = 0.56 (0.38, 0.84) ARR = 0.80% NNT = 125

p=0.004

1.84%

1.04%

Parenteral Therapy

Visi

t 3

VTE Prevention – Extended Therapy

Major bleeding events (ISTH) through 7 days after drug discontinuation

0.0

0.2

0.4

0.6

0.8

1.0

Enoxaparin (N=3,716) Betrixaban (N=3,716)

Eve

nt ra

te (%

)

n=21

0.57% 0.67%

p = 0.55

n=25

Gibson et. al. ISTH SSC 2016 – May 27, 2016

VTE Prevention – Extended Therapy

APEX trial key inclusion criteria: Age/Risk Factors:

− ≥ 75 yo OR − 60 - 74 yo with D-dimer ≥ 2x ULN OR − 40 - 59 yo with D-dimer ≥ 2x ULN and a history of either VTE, or cancer*

Anticipated to be severely immobilized for at least 24 hours after randomization with anticipated length of hospitalization ≥ 3 days

Hospitalized for one of the following acute presentation:

− Acute on chronic heart failure decompensation − Acute on chronic respiratory failure − Acute infection without septic shock − Acute rheumatic disorders − Acute ischemic stroke (w/ immobilization)

Atrial Fibrillation and Stroke Prevention

Increases with age Prevalence and Projections 2002 - 2050

Atrial Fibrillation and Stroke Prevention

100,000‒125,000 embolic AF-related strokes/year

Most AF-related strokes are preventable with appropriate anticoagulant therapy

Non-valvular Atrial Fibrillation

Nonvalvular Atrial Fibrillation (NVAF) is AF that occurs in the absence of either: a mechanical prosthetic heart valve or moderate to severe mitral stenosis Important because patients with mechanical heart valves and significant mitral stenosis were excluded from recent trials

Valvular Atrial Fibrillation

Eikelboom et al. randomized 252 patients from 39 centers to receive dabigatran or warfarin in a 2:1 ratio. The trial was terminated early based on interim analysis of composite of stroke, systemic embolism, myocardial infarction and death: 8% in the dabigatran group and 2% in the warfarin group (hazard ratio: 3.37; 95% CI: 0.76–14.95; p = 0.11).

Anticoagulant Recommendations in NVAF Based on CHA2DS2-VASc

ACC AnticoagEvaluator App CHA2DS2-VASc

Anticoagulant Recommendations in NVAF Based on CHA2DS2-VASc

Score stroke risk by CHA2DS2-VASc

CHA2DS2-VASc > 1

Oral anticoagulant (OCA)

CHA2DS2-VASc = 1

No Therapy OR

Treatment with OAC OR

Aspirin

CHA2DS2-VASc = 0

NO Antithrombotic

Therapy

Role of Aspirin in Reducing Stroke in Atrial Fibrillation

Major effect was on minor, non-disabling stroke (less likely to be cardioembolic) For disabling or fatal stroke OR 0.86, 95% (CI 0.50 through 1.49)

Dual Anti-Platelet Therapy in Reducing Stroke in AF ACTIVE A: ~7500 patients with AF for whom OAC was unsuitable

Relative risk of stroke 0.72 for C+A versus ASA alone (p<0.001).

ACTIVE W: ~6700 patients with AF randomized to warfarin or clopidogrel + aspirin (C+A)

Relative risk of stroke 1.44 for C+A versus OAC (p<0.001).

Bleeding with Dual Anti-Platelet Therapy in AF

0.0

0.01

0.02

0.03

0.04

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASA

Lancet 2006; 367: 1903-12

Cum

ulat

ive

Haz

ard

Rat

es

Years

2.4 %/year

2.2 %/year

RR = 1.06

P = 0.67

Major Bleeding in ACTIVE W

Review of DOACs in AF Stroke or Embolization

Real World Experience – US Claims Database

Review of DOACs in AF Bleeding

Real World Experience – US Claims Database

Aristotle Trial: Bleeding

Major Bleeding with OAC and Anti-Platelet Therapy

Bleeding Management Considerations

• FFP does not reverse DOAC effect Can consider as fluid/replacement

• Vitamin K does not reverse DOAC effect • Apixaban, rivaroxaban, edoxaban have no FDA-approved antidote at this time

Current practice is to give 4-factor PCC (Kcentra/off-label use: 25-50 IU/kg) No data about additional benefit of aPCC (Feiba®) 50 U/kg; max 200 U/kg/d or rFVIIa (NovoSeven®) 90 µg/kg

• Dabigatran Idarucizumab 5 g IV (2 consecutive 2.5 g IV infusions no more than 15 min apart)

Bleeding Management Considerations

Non-specific reversal strategies • PCC (Factors II, VII, IX, and X) as non-activated PCC 50u/kg (e.g.

KCentra) or activated 80u/kg (e.g. FEIBA) • Limited to in-vitro studies, animal models, or healthy volunteers • Conflicting results • Evidence remains low quality, limited data on clinical outcomes

(hemostasis, mortality) • Recombinant Factor VIIa is generally not recommended as first line

agent for DOAC reversal

2017 status: Further comparative effectiveness studies are needed to understand the risks/benefits of PCC for DOAC reversal

QUESTIONS ?

Role of Left Atrial Appendage (LAA) Occlusion

Percutaneous Approaches WATCHMAN LARIAT Amplatzer (not FDA approved) Surgical Approaches

LAA Occlusion with WATCHMAN

LAA Occlusion with WATCHMAN

FDA approval: To reduce the risk of thromboembolism from the LAA in patients with nonvalvular atrial fibrillation who: • Are at increased risk of stroke and systemic embolism and for whom

anticoagulation therapy is recommended; • Have physician approval to take warfarin; and • Have an appropriate reason to want treatment with a non-medication

alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

PROTECT TRIAL: Watchman vs. warfarin randomized 2:1 in 707 patients with AF (mean CHA2DS2-VASc = 3.5). PREVAIL: Watchman vs. warfarin in 407 patients with AF (mean CHA2DS2-VASc = 3.8). Meta-analysis

LAA Occlusion with WATCHMAN

LAA Occlusion with WATCHMAN