ANTITHROMBOTIC THERAPY FOR VTE DISEASE : CHEST GUIDELINES 2016

CASEA 44-year-old man is evaluated in follow-up for an episode of

unprovoked left proximal leg deep venous thrombosis 3 months ago. Following initial anticoagulation with low-molecular-weight heparin, he began treatment with warfarin. INR testing done every 3 to 4 weeks has shown a stable therapeutic INR. He has mild left leg discomfort after a long day of standing, but it does not limit his activity level. He tolerates warfarin well. Family history is unremarkable, and he takes no other medications.

Which of the following is the most appropriate management?

A. Continue anticoagulation indefinitelyB. Discontinue warfarin in another 3 monthsC. Discontinue warfarin nowD. Discontinue warfarin and perform thrombophilia

testing

OBJECTIVES Review of anticoagulants Recognize subgroups of VTE Review guidelines for duration of therapy Understand differences in therapy based on type of

VTE

Subgroups of VTE

Cancer-associated vs No cancer Provoked vs Unprovoked Proximal vs Distal DVT Upper extremity vs Lower extremity DVT

PROVOKED Reversible cause-surgery , pregnancy ,

immobilization Irreversible causes – magnancy , indefinite

hypercoagulable states Unprovoked Unidentifiable causes

Classification of Anticoagulants

Parental Anticoagulants Dosing

UFH80 U/kg IV bolus followed by 18 U/kg/hr5000U IV bolus followed by 1000 U/hrEnoxaparin1 mg/kg SQ Q12H1.5 mg/kg SQ QDCrCl < 30: 1 mg/kg SQ Q24HFondaparinux< 50kg: 5mg SQ QD50-100kg: 7.5mg SQ QD> 100kg: 10mg SQ QD

Unfractioned Heparin 80 U/kg IV bolus followed by 18 U/kg/hr 5000U IV bolus followed by 1000 U/hr Enoxaparin 1 mg/kg SC 12H CrCl < 30: 1 mg/kg SC 24H Fondaparinux < 50kg: 5mg SC OD 50-100kg: 7.5mg SC OD > 100kg: 10mg SC OD

Tinzaparin175 U/kg SC ODCrCl < 30: use with cautionNadroparin171 U/kg SC ODCrCl 30-50: reduce dose by 25-33%CrCl < 30: use with caution

Oral Anticoagulants TherapyVitamin K Antagonist - warfarinStarted on day 1 or 2 of parenteral anticoagulationMaintain overlap for at least 5 days.INR goal = 2-3Many diet, drug, and disease interactions

ORNOAC Rivaroxaban, Apixaban, Edoxaban, DabigatranPreferred VTE treatment

RivaroxobanDosingDVT/PE treatment: 15mg BD x 21 days followed by 20mg ODTake with foodExtremes in weight do not influenceDoes not require parenteral anticoagulation prior to initiationReduction in risk of recurrence: 20mg ODRenal and hepatic impairment

Cr Cl < 30: avoid use Moderate-severe hepatic impairment: avoid use

Discontinuation for surgery or other procedures Stop rivaroxaban at least 24 hours before procedure Restart rivaroxaban after surgery/procedure as soon as adequate

hemostasis is established Switching to rivaroxaban From warfarin to rivaroxaban: Discontinue warfarin and start rivaroxaban as

soon as INR is below 3.0 From anticoagulant other than warfarin to rivaroxaban: Start rivaroxaban 0 to

2 hours prior to next scheduled evening administration of the drug and omit administration of the other anticoagulant

From unfractionated heparin continuous infusion to rivaroxaban: Stop infusion and start rivaroxaban at the same time

APIXABANDosingDVT treatment: 10mg BD x 7 days followed by 5mg BDDoes not require parenteral anticoagulation prior to initiationReduction in risk of recurrence: 2.5mg BD Renal impairment

CrCl < 30: use with caution Nonvalvular atrial fibrillation Decrease dose to 2.5 mg PO BD in patients with any 2 of the

following characteristics: Age ≥80 years Weight ≤60 kg Serum creatinine ≥1.5 mg/dL

Hepatic impairment Mild : No dosage adjustment required Moderate/Severe: Not recommended Surgery/procedures Discontinue at least 48 hr before elective surgery or invasive

procedures with a moderate or high risk of unacceptable or clinically significant bleeding

EDOXABAN DVT or PE Treatment Indicated for treatment in patients who have been initially treated with

a parenteral anticoagulant for 5-10 days >60 kg: 60 mg PO OD ≤60 kg: 30 mg PO OD

Renal impairment (DVT/PE) >50 mL/min: No dosage adjustment required 15-50 mL/min: 30 mg PO OD Renal impairment (NVAF) CrCl >95 mL/min: Do not use; increased ischemic stroke compared with

warfarin CrCl >50 to 95 mL/min: No dosage adjustment required CrCl 15-50 mL/min: 30 mg PO OD

Hepatic impairment Mild (Child-Pugh A): No dose adjustment required Moderate-to-severe (Child-Pugh B/C): Not recommended; Transition to edoxaban From warfarin or other vitamin K antagonists (VKAs): Discontinue

warfarin and start edoxaban when INR ≤2.5 From oral anticoagulants other than warfarin or other VKAs:

Discontinue current oral anticoagulant and initiate edoxaban at the time of the next scheduled dose of the previous oral anticoagulant

From low molecular weight heparin (LMWH): Discontinue LMWH and initiate edoxaban at the time of the next scheduled administration of LMWH

From unfractionated heparin: Discontinue heparin infusion and initiate edoxaban 4 hr later

DABIGATRAN DVT or PE Treatment Indicated for patients who have been treated with a parenteral anticoagulant for 5-10

days CrCl >30 mL/min: 150 mg PO BD CrCl ≤30 mL/min or on dialysis: not indicated Stroke Prophylaxis With Atrial Fibrillation Prevention of stroke and systemic embolism associated with nonvalvular atrial

fibrillation CrCl >30 mL/min: 150 mg PO BID CrCl 15-30 mL/min: 75 mg PO BID CrCl <15 mL/min or dialysis: not recommended

Discontinuation for surgery and other interventions Discontinue dabigatran 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days

(CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding

Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required

NOAC Parenteral needed

Weight adj Unique Reversal

Rivaroxaban No No Take with food

No

Apixaban No ~ No Pregnancy B No

Edoxaban Yes Yes CrCl > 95: avoid

No

Dabigatran Yes No GI upset Praxbind, dialyzable

NOAC Evidence4 new RCTs and extensive clinical experienceRisk reduction similar between NOACs and VKARisk reduction greater with LMWH than VKA in patients with cancerRisk reduction seems to be similar between all NOACs (No direct comparison)Risk of bleeding less with NOACs than VKAGI bleeding may be higher, thoughRisk may be less with apixabanRisk of fatal bleeding similar between VKA and NOACsConclusion, less bleeding and greater convenience with NOACs

Choice of Anticoagulant

DVT/PE and no Cancer: NOAC>VKA>LMWH

DVT/PE and Cancer:

LMWH>VKA>NOAC

Duration of anticoagulantsFour durations of treatment: (1) 4 or 6 weeks; short term (2) 3 months; long term(3) longer than 3 months but still a time-limited course of therapy(usually 6 or 12 months); or (4) extended (also termed “indefinite”; no scheduled stopping date) therapy

RISK FACTOR RATE OF RECURRENCE

SURGERY 3 % AT 5 YEARS

NON SURGICAL 15 % AT 5 YEARS

UNPROVOKED 30 % AT 5 YEARS

CANCER 15 % ANNUAL RISK

Risk Factors for Bleeding on Anticoagulant Therapy

Age >65Previous bleedingCancerMetastatic cancerRenal failureLiver failureThrombocytopeniaPrevious strokeDiabetesAnemiaAntiplatelet therapyPoor anticoagulant controlNSAID use

Low risk 0 risk factorsModerate risk 1 risk factor

High risk ≥2 risk factors

In patients with a proximal & distal DVT of the leg or PE provoked by surgery or non surgical transient risk factor,

Treatment with anticoagulation for 3 months is preferred over

(i) treatment of a shorter period , (ii) treatment of a longer, time-limited period (eg 6, 12, or 24 months) , or (iii) extended therapy (no scheduled stop date) ..

In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE should have atleast 3 month anticoagulant therapy

(i) low or moderate bleeding risk ,extended anticoagulant therapy > long term (ii) high bleeding risk , long term > extented therapy

In patients with a second unprovoked VTE and who have a (i) low and moderate bleeding risk , extended anticoagulant therapy > long term (ii) high bleeding risk , long term > extented therapy

In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who do not have a high bleeding risk, recommendation are extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy .

Aspirin for Extended Treatment of VTE

In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, aspirin over no aspirin to prevent recurrent VTE is suggested

These recommendations are based on two randomized trials. Extended anticoagulant therapy reduce recurrent VTE by more than 80% and Aspirin by 33 % .

Whether and How to Prescribe Anticoagulants to Patients With Isolated Distal DVT

Two management options for isolated DVT

1) treat patients with anticoagulant therapy or

2) follow-up US examination (eg, after 1 and 2 weeks, or sooner if there is concern )

Risk factors for extension of distal DVT that would favor anticoagulation over surveillance:(1) D-dimer is positive (2) thrombosis is extensive (eg, >5 cm in length, involves multiple veins, >7 mm in maximum diameter);(3) thrombosis is close to the proximal veins;(4) there is no reversible provoking factor for DVT; (5) active cancer;. (6) history of VTE; and(7) inpatient status.(8) Severe symptoms(9) DVT that are detected using a selective approach to whole-leg US

Surveillance over anticoagulation 1) thrombosis that is confined to the muscular veins of the calf ( soleus,

gastrocnemius) to have a lower risk of extension than thrombosis that involves the axial ( ie, true deep; peroneal, tibial ) veins.

2) high bleeding risk 3) whereas distal DVT detected by routine whole-leg US

In patients with acute, isolated, distal DVT of the leg who are managed with serial imaging,

(i) no anticoagulation if the thrombus does not extend

(ii) suggest anticoagulation if the thrombus extends but remains confined to the distal veins or extends into the proximal veins

CDT for Acute DVT of the Leg

In patients with acute proximal DVT of the leg, anticoagulant therapy alone over CDT is preferred.

It was based on various randomized trials and cavenent study (Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis Study) which shows CDT is associated with an increase in transfusion (twofold), intracranial bleeding (threefold),PE (1.5-fold), and vena caval filter insertion (twofold);

CDT is preferred over anticoagulation in patients having

1) Iliofemoral DVT, 2) Symptoms for <14 days,3) Good functional status, 4) Life expectancy of >1 year, and 5) low risk of bleeding

Role of IVC Filter for Acute DVT or PE

In patients with acute DVT or PE who are treated with anticoagulants, recommendations are against the use of an IVC filter.

These recommendations are based on PREPIC 1 and PREPIC 2 trial (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) which showed placement of a permanent IVC filter increased DVT, decreased PE, and did not influence VTE (DVT and PE combined) or mortality

Compression Stocking to Prevent PTS

In patients with acute DVT of the leg , compression stockings routinely to prevent PTS are not recommended

These were based on findings of two small, single-center, randomized trials in which patients and study personnel were not blinded to stocking use (non placebo stocking) .

Subsegmental PE

Subsegmental PE refers to PE that is confined to the subsegmental pulmonary arteries.There is uncertainty whether these patients should be anticoagulated for two reasons :

First because of false positive findings

Second, because a true subsegmental PE arises from a small DVT, the risk of progressive or recurrent VTE without anticoagulation is expected to be lower.

.

Diagnosis of subsegmental PE(1) the CT pulmonary angiogram is of high quality with good opacification of the distal pulmonary arteries; (2) there are multiple intraluminal defects; (3) defects involve more proximal subsegmental arteries (ie, are larger);(4) defects are seen on more than one image; (5) defects are surrounded by contrast rather than appearing to be adherent to the pulmonary artery walls; (6) defects are seen on more than one projection; (7) patients are symptomatic, as opposed to PE being an incidental finding; (8) there is a high clinical pretest probability forPE;(9) D-dimer level is elevated, particularly if theincrease is marked and otherwise unexplained.

Other risk factors for VTE in pt of subsegmental PE are thepatients who are 1.hospitalized or2. Reduced mobility 3. Active cancer (particularly if metastatic or being treated with chemotherapy); 4. No reversible risk factor for VTE such as recent surgery.

Favors anticoagulation

In patients with subsegmental PE (no involvement of more proximal pulmonary arteries) and no proximal DVT in the legs who have a (i)low risk for recurrent VTE clinical surveillance over anticoagulation is suggested (ii) high risk for recurrent VTE , anticoagulation over clinical surveillance

Treatment of Acute PE Out of the Hospital

Patients who satisfy all of the following criteria are suitable for treatment of acute PE out of the hospital:(1) clinically stable with good cardiopulmonary reserve;(2) no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, <70,000/mm3); (3) expected to be compliant with treatment; and(4) the patient feels well enough to be treated at home.

Systemic Thrombolytic Therapy for PE

Pulmonary Embolism Thrombolysis trial, which randomized 1,006 patients with PE and right ventricular dysfunction showed that thrombolytic therapy prevented cardiovascular collapse but increased major (including intracranial) bleeding; with no convincing net benefit from thrombolytic therapy. However favored “rescue thrombolytic therapy” on patients who developed cardiovascular collapse after initially being treated with anticoagulant therapy alone

PE With Hypotension AT 10 suggsts that thrombolytic thearapy over

anticoagulation in pt with acute PE with hypotension (ie, systolic BP <90 mm Hg for 15 min) and without high bleeding risk.

PE Without Hypotension

In most patients with acute PE not associated with hypotension, recommendations are against systemically administered thrombolytic therapy

In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, thrombolytic therapy is suggested.

Indications of thrombolytic therapy1.Progressive increase in heart rate, 2.Decrease in systolic BP (which remains >90 mm Hg), 3. Increase in jugular venous pressure, 4. Worsening gas exchange, 5.Signs of shock (eg, cold sweaty skin, reduced urine output, confusion), 6. Progressive right heart dysfunction on echocardiography, or an 7. Increase in cardiac biomarkers.

Catheter-Based Thrombus Removal for theInitial Treatment of PE

In patients with acute PE who are treated with athrombolytic agent, systemic thrombolytictherapy using a peripheral vein over CDT is recommended

In patients with acute PE associated with hypotensionand who have (i) a high bleeding risk,(ii) failed systemic thrombolysis, or (iii) shock that islikely to cause death before systemic thrombolysiscan take effect (eg, within hours), CDT > NO THERAPY

Thrombolytic Therapy in Patients With UpperExtremity DVT

Thrombolysis is most likely to be of benefit in patients who meet the following criteria:1. severe symptoms2.thrombus involving most of the subclavian vein and the axillary vein;3.symptoms for <14 days;4.Good functional status;5.life expectancy of >1 year; and 6.Low risk for bleeding.

In patients with UEDVT who undergo thrombolysis, same intensity and duration of anticoagulant therapy as in patients with UEDVT who do not undergo thrombolysis

Management of Recurrent VTE onAnticoagulant Therapy

Unusual occurrence so reevaluate: Diagnosis Compliance Underlying malignancy

If occurs while on therapeutic VKA or NOAC therapy, suggest switching to LMWH therapy at least temporarily and for at least 1 monthIf occurs while on long-term LMWH, suggest increasing dose by 1/4 -1/3

SUMMARY Non-Cancer: NOAC > VKA > LMWH Cancer: LMWH Recurrent: Switch to LMWH or increase LMWH dose Provoked risk factor : long term > extented / short term Unprovoked / cancer : extented > long term Thrombolytic: only in massive or deteriorating PE Compression stockings: do not routinely use Subsegmental [PE: base therapy on risk Aspirin > no aspirin in unprovoked dvt Isolated distal dvt : severe symptoms or risk fctors anticoagulation

> surviellance. PE with hypotension and progressive worsening on anticoagulant

therapy thrombolytic therapy > anticoagulation