Diagnostic and Therapeutic Approach to Venous Thromboembolism

Dr. Mark Choi, MDGeneral Internal MedicineAbbotsford Regional Hospital and Cancer Centre

Disclosure

Bayer Inc.

Pulmonary Embolism

VTE incidence in total population is ~100/100 000 patients/year

1/3 of VTE cases are PE

Acute PE has an estimated 30-day mortality ranging from 5 to 30%1

Causes ~300,000 deaths in the United States and over 500,000 deaths in Europe per year2,3

In the EU, more than twice as many people die from VTE than from AIDS, breast cancer, prostate cancer and transportation accidents combined3

296,370543,454

• Régie de l'assurance maladie du Québec (RAMQ) retrospective health database review study suggests that the overall incidence of first definite or probable PE event is 4.5/10,000 person-years4

• 15,700 annual incident cases of PE across Canada4

DVT: Distal or Proximal DVT can be:

Distal Below the knee in the deep

veins of the calf Proximal

Above the knee, primarily in the popliteal and femoral veins

DVT usually begins distally A thrombus may grow and extend

to the proximal veins and embolize1

Risk of recurrence or extension is greater for proximal DVT’s 2

External iliac

Anterior tibial

Popliteal

Great saphenous

Deep femoral

Posterior tibial

Dorsal venous arch

Distal

Pro

ximal

Venous Thromboembolism Deep Vein Thrombosis

Diagnostic Algorithm / Wells Criteria for DVT Are isolated distal DVTs treated the same way as above

knee DVTs? Are superficial vein thromboses ever treated with OAC? Iatrogenic venous thrombosis Treatment and its duration Congenital workup

Pulmonary Embolism Diagnostic Algorithm / Wells Criteria for PE Is CT chest always superior to VQ scan? What is the VQ criteria?

Treatment Options Warfarin vs. NOACs (dabigatran and rivaroxaban) Pros and Cons of NOACs

Deep Vein Thrombosis

Diagnostic Approach

Scarvelis D , and Wells P S CMAJ 2006;175:1087-1092

Well’s Criteria for DVT 1 point each for below:

Paralysis, paresis or recent orthopedic casting of lower extremity

Recently bedridden (> 3 days) or major Sx within 4 weeks

Localized tenderness in deep vein system Swelling of entire leg Calf swelling 3cm greater than other leg (measured 10cm

below the tibial tuberosity) Pitting edema greater in the symptomatic leg Collateral non-varicosesuperficial veins Active cancer or cancer treated within 6 months

-2 points for alternative more likely diagnosis (baker’s cyst, cellulitis, muscle damage, SVT, post-thrombotic syndrome, inguinal lymphadenopathy, external venous compression)

Isolated Distal DVT Conflicting studies. Extension to proximal veins noted

in 4 to 16% of patients without treatment; 7 to 10% of PE’s found to have isolated distal DVTs

Issues: Fewer late sequelae than proximal DVT Operator dependent Less sensitive than proximal vein examination

Major risk factor for extension was active cancer Isolated distal DVT had lower rate of recurrence

whereas bilateral distal DVT had same recurrence as proximal DVT

Current guideline: treat for 3 months

Superficial Vein Thrombosis Treatment

Elevation of affected limb Warm and cold compresses Topical or oral NSAID’s Encourage ambulation

Treat pts with OAC (3 months) in higher risk for extension

High risk features: Affected vein segment > 5cm,

saphenofemoral/saphenopopliteal junction, < 5cm to deep venous system, medical risk factors Chest. 2008;133(6 Suppl):454S

Catheter-related venous thrombosis

Risk of thrombosis present with central (CVCs) and peripheral catheters (PICCs)

Most patients are asymptomatic Higher risks of thrombosis with PICCs (both

peripheral and central venous thrombsis) RFs for CRVT = mal-positioned catheter,

larger diameter catheters, active cancer, prior hx of DVT, hormonal therapy and congenital VTE predisposition

Catheter-related venous thrombosis Superficial phlebitis

Remove catheter Elevate affected limb Warm or cold compresses Topical or oral NSAIDs Repeat U/S in 1 week in patients with RF’s

Upper extremity DVT OAC as long as the catheter is in situ and

consider longer depending on RFs If OAC is discontinued, repeat U/S to look for

extension in patients with RFs

Treatment of proximal/distal DVT Provoked DVT = treat for 3 months Unprovoked DVT = treat for 3 months and

consider longer Rebound DVT = Risk roughly 20% in 2 years

after discontinuation of OAC. Follow-up Baseline DVT and d-dimer necessary

at the end of treatment with OAC in order to differentiate between recurrent DVT and post-thrombotic syndrome if his/her symptoms return

Congenital workup = reserved for unprovoked VTE’s in younger patients or strong family history of VTE

Pulmonary Embolism

Pulmonary Embolism Diagnostic approach that we are used to:

RYU JH, SWENSEN SJ, OLSON EJ, PELLIKKA PA. DIAGNOSIS OF PULMONARY EMBOLISM WITH USE OF COMPUTED TOMOGRAPHIC ANGIOGRAPHY. MAYO CLIN PROC 2001;76:63.

Wells Criteria for PE Alternative diagnosis less likely than PE 3.0 Signs or symptoms of DVT 3.0 History of PE or DVT 1.5 Immobilization for at least 3 days or surgery 1.5in the previous month Heart rate >100 beats/min 1.5 Hemoptysis 1.0 Active cancer (treatment ongoing, within 1.0previous 6 months or palliative)

For high sensitivity D-dimer:Low probability: <2 pointsIntermediate probability: 2–6 pointsHigh probability: ≥6 points

Is CT chest superior to VQ scan?

Initial VQ study showed good sensitivity and specificity to the gold standard (pulmonary angiogram)

CTPA compared to VQ study and deemed non-inferior to VQ for diagnosis of PE

Pros and Cons of CT Chest CT chest with IV contrast

Pros Non-inferior to VQ scan in diagnosis of PE May catch other pulmonary findings (pneumonia, mass,

emphysema, ILD etc) Cons

Radiation exposure (ei. Pregnancy) Risk of contrast-induced nephropathy in kidney dz May give indeterminate findings

Patient may move during the study IV contrast timed incorrectly

Incidental findings of isolated subsegmental PE may lead to over-treatment

Potential risk of allergy to IV contrast dye

Pros and Cons of VQ Scan VQ Scan

Pros Good sensitivity and specificity in comparison to gold

standard (pulmonary angiogram) May catch other pulmonary findings (focal

consolidation) Safe in kidney disease Relatively small radiation exposure (equiv ~ 5 CXRs)

Cons May give indeterminate findings

If performed in patients with chronic cardiac or pulmonary disease

Availability: nuclear medicine open daytime Mon to Fri in most tertiary centres

Radiation Exposure

64-slice CTPA delivers 50-60mSv to the breast

V/Q Scan delivers only 0.28-0.9mSv In comparison, a 2-view mammogram

is associated with 3mSv Radiation exposure to female breast

is 70 to 100-fold greater in CTPA vs. V/Q scan

Einstein AJ. Estimating risk of cancer associated with radiation exposure from 64-slice CT angiography. JAMA. 2007; 298: 317-323Parker MS. Female breast radiation exposure during CT pulmonary angiography. Am J Radiol. 2005. 185: 1229-1233 Cook JV. Radiation from CT and perfusion scanning in prengnancyTask Group on Control of Radiation Dose in CT: a report of the International Commission on Radiological Protection. AnnICRP 2000;30:7-45

Radiation Exposure

There is non-negligible increase in lifetime attributable risk of cancer, particularly to the breasts of young women 1 in 143 for a 20-year-old woman 1 in 284 for a 40-year-old woman

There is also increased odds of lung cancer in both gender

Einstein AJ. Estimating risk of cancer associated with radiation exposure from 64-slice CT angiography. JAMA. 2007; 298: 317-323

When do physicians choose VQ Scan?

In the setting of decreased eGFR Known IV contrast allergy When CTPA result is indeterminate Pregnancy and Post-Partum Because it causes less radiation

So when is V/Q scan more appropriate to order over a CT scan?

younger population female population no other intrathoracic disease is

suspected decreased eGFR Pregnancy/Post Partum Consider in those meeting the “VQ

criteria”

The VQ Criteria

There are 2 VQ Criteria A normal CXR No history of chronic lung disease or

congestive heart failure If above 2 criteria are met, it is very

unlikely that the VQ scan will give an indeterminate finding

V/Q vs. CTPE Study Data on all CT and V/Q scans performed to

assess for PE in St. Michael's Hospital (SMH) inpatients over 2-year period collected

Exclusion CT scans ordered at hours when V/Q scan is

unavailable (weeknights, weekends and holidays) were excluded

CT scans looking for PE and other diagnoses were excluded

CT scans ordered on intensive care patients were excluded.

V/Q vs. CTPE Study

29.2% of CTPE studies met the V/Q criteria

Reasons for choosing V/Q Scan

V/Q Scan as primary imaging modality

Only half (14 of 28) of these studies met the VQ Criteria

V/Q vs. CTPE study conclusion

V/Q scan under-utilized in patients meeting V/Q criteria

Not using the V/Q criteria leads to many indeterminate findings

Preferred AlgorithmPre-test Probability using Dichotomized Well’s Score

Low (4 or less) High (5 or higher)

D-dimer Normal CXR and no hx of cardiopulmonary disease

Yes NoHigh (>500)Low (< 500)

PE ruled out

VQ Scan

CT ScanIf either test indeterminate

Renal Dysfunction or IV contrast allergy

Yes No

Case Scenarios

Case 1 29 year-old female with acute left-sided

pleuritic chest pain with dyspnea and palpitations. No leg symptoms

PMH: none; FmHx: none HR 120bpm. Afebrile. SpO2 86% on RA Investigation:

ECG = sinus tachy CXR PA+lateral = nil acute D-dimer 1200

Imaging Modality?

Case 2 75 year old with acute right-sided pleuritic

chest pain, wheezing and SOB. No leg symptoms

PMH: COPD, HTN. HR = 105bpm, temp 39.1C SpO2 82% on

RA, Resp: bilateral wheezing Investigation

CXR = new right middle lobe consolidation D-dimer = 790 Cr = 180

Imaging Modality?

Case 3 45 year-old woman with acute right-sided

pleuritic chest pain with SOB. No leg symptoms PMH: CHF (35%), HTN , chol, DM HR: 109 bpm, temp = 36.5C, Sp02 = 88% RA Investigation:

CXR = cardiomegaly, trace bilateral effusion ECG = rapid AF D-dimer = >4000 Cr = 80

Imaging Modality?

Case 4 45 year-old woman with acute right-sided

pleuritic chest pain with SOB. No leg symptoms

PMH: CHF (35%), HTN , chol, DM HR: 109 bpm, temp = 36.5C Investigation:

CXR = cardiomegaly, trace bilateral effusion ECG = rapid AF D-dimer = >4000 Cr = 220

Imaging Modality?

Treatment Options

Treatment Options Warfarin

vitamin K antagonist IV heparin

binds AT and inactivates fXa and prevents conversion of fibrinogen to fibrin

LMWH binds AT and inactivates fXa

fondaparinux enhances the anti-Xa activity of AT by 300-fold

NOAC’s Dabigatran (direct thrombin inhibitor) Rivaroxaban (direct factor Xa inhibitor) Apixaban (not approved in Canada for treatment of PE or DVT

yet) IVC filter Intravenous thrombolytics

Warfarin is Highly Effective for the Prevention of Stroke in AF or Recurrent VTE

1. Hart et al Ann Intern Med. 2007;146:857-867; 2. Connolly et al. Lancet. 2006;367:1903-12; 3. Line B. Semin Nucl Med. 2001;31:90–101 4. Kearon C. Circulation 2003;107:I22–I30.

Stroke Prevention in Atrial Fibrillation

Treatment of Venous Thromboembolism (VTE)

47%If proximal DVT inadequately treated3

Chance of recurrent VTE in first 3 months

1

1

2

<2%If adequate anticoagulant

response is achieved4

Standard Care: Warfarin (INR 2.0-3.0) Standard Care: Warfarin (INR 2.0-3.0), initial parenteral anticoagulation until INR >2

Properties of an Ideal Anticoagulant vs. Currently Available Agents

IDEAL LMWH UFH VKA NOAC

Oral

No significant food/drug interactions

Predictable response

No requirement for coagulation monitoring

Fixed dosing

No HIT

Cost

Reversible

HIT: Heparin induced thrombocytopenia

?

Canadian Approvals of New Oral Anticoagulants

2008 201120102009

RivaroxabanVTE prophylaxis following THR/TKR

20132012

Health Canada NOC database: http://webprod5.hc-sc.gc.ca/noc-ac/index-eng.jsp

DabigatranVTE prophylaxis following THR/TKR

ApixabanVTE prophylaxis following THR/TKR

DabigatranStroke prevention in AF

RivaroxabanStroke prevention in AF

RivaroxabanTreatment and secondary prevention of DVT (2012) and PE (2013)

New oral anticoagulants

DabigatranTreatment and secondary prevention of DVT and PEApixaban

Stroke prevention in AF

2014

Novel Oral Anticoagulants – Pharmacological Properties

Characteristic Rivaroxaban1 Dabigatran2 Apixaban3

Target Factor Xa Factor IIa Factor Xa

Dosing OD BID BID

Bioavailability, % 80-100%* 6.5% 50%

Half-life 5-13h 12-14 h 8-15 h

Renal clearance (unchanged bioavailable drug)

~33% 85% 27%†

Cmax 2-4 h 1-2 h 3-4 h

Bridging with LMWH

No Yes No

* When the 15mg and 20mg dose is taken with food† Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine

1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review

New Oral Anticoagulants: Total Drug Exposure (AUC) with Declining Renal Function

Rivaroxaban (33% cleared renally*)1

Dabigatran(85% cleared renally)2

Apixaban(27% cleared renally†)3

* active drug† Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review

Landmark DVT/PE TrialsPhase II Phase III

Rivaroxaban Oral, direct Factor Xa inhibitor

EINSTEIN DVT2

Rivaroxaban vs LMWH/UFH followed by VKA

ODIXa-DVT3

Rivaroxaban vs enoxaparin followed by VKA

EINSTEIN DVT/PE5,6

Rivaroxaban for 3, 6 or 12 months vs enoxaparin for ≥5 days followed by VKA for 3, 6, or 12 months

EINSTEIN EXT5

Pre-treatment with rivaroxaban or VKA for 6 or 12 months followed by rivaroxaban or placebo for 6 or 12 months

Dabigatran Oral, direct thrombin inhibitor

RE-COVER7 & RE-COVER II8

5–10 days pre-treatment with LMWH bridging to dabigatran or VKA for 6 months

RE-MEDY9

3–6 months’ treatment with approved anticoagulant; switch to dabigatran or VKA

RE-SONATE10

6–18 months’ VKA treatment followed by 6 months dabigatran or placebo

ApixabanOral, direct Factor Xa inhibitor

Botticelli-DVT4

Apixaban vs LMWH or fondaparinux followed by VKA

AMPLIFY1

Apixaban 10 mg bid followed by 5 mg bid for 6 months vs. enoxaparin followed by VKA

AMPLIFY-EXT11

Apixaban 2.5 mg bid or 5 mg bid for extended 12 months period vs placebo

1. http://clinicaltrials.gov; 2. Buller HR et al. Blood 2008; 3. Agnelli GA, et al. Circulation 2007; 4. Büller HR, et al. J Thromb Haemost 2008; 5. The EINSTEIN Investigators. N Engl J Med 2010; 6. The EINSTEIN–PE Investigators. N Engl J Med 2012; 7. Schulman S, et al. N Engl J Med 2009; 8. Schulman S, et al. ASH Annual Meeting Abstracts. Blood 2011; 9. Schulmann S et al. ISTH 2011; 10. Schulman S, et al. ISTH 2011; 11. Agnelli G et al. N Engl J Med 2012; 12. Raskob G et al. J Thromb Haemost. 2013.

Bridging with LMWH and duration of treatment are the main differences between the trialsThe following slides summarize trial results with NOACs in VTE treatment

Not intended as cross-trial comparison

VTE treatment Results comparison: pivotal phase III clinical trials – Efficacy

Study drug n (%)

LMWH/VKAn (%)

ARD%

HR 95% CI P

EINSTEIN

Pooled

3, 6, 12 months

86 (2.1) 95 (2.3)

0.2 0.89 0.66-1.19

N-inf

RE-COVER

Pooled

6 months

(2.7) (2.4) -0.3 1.09 0.77-1.54

N-inf

AMPLIFY

6 months

59 (2.3) 71 (2.7)

0.4 0.84 0.60–1.18

N-inf

Recurrent VTE or VTE-related death

Hazard ratio and 95% CIs

Favours study drug

Favours LMWH/VKA

* Event during on-treatment period

Hazard ratio and 95% CIs

Favours study drugFavours

LMWH/VKA

VTE treatment Results comparison: pivotal phase III clinical trials – Safety

Major BleedingStudy drug n (%)

LMWH/VKAn (%)

ARR%

HR 95% CI P

EINSTEIN

Pooled

3, 6, 12 Months

40 (1.0) 72 (1.7) 0.7 0.54 0.37-0.79 Sup.

RE-COVER

Pooled

6 months

37 (1.4) 51 (2.0) 0.6 0.73 0.48-1.11 N-inf

AMPLIFY

6 months

15 (0.6) 49 (1.8) 1.2 0.31 0.17–0.55 Sup.

Hazard ratio and 95% CIs

Favours study drugFavours

LMWH/VKA

Summary Main Phase

Few differences in trial designs Bridging with LMWH in RE-COVER vs. Single-

drug approach in EINSTEIN and AMPLIFY Duration of treatment – 6 months in RE-COVER

and AMPLIFY vs. 3, 6 or 12 months in EINSTEIN OD in EINSTEIN (after initial acute phase for

EINSTEIN) vs. BID in RE-COVER and AMPLIFY All agents were non-inferior vs. warfarin in preventing

VTE recurrence Rivaroxaban and apixaban were superior to warfarin

in reducing major bleeding whereas dabigatran was non-inferior

Cost of NOAC’s May apply for Special Authority for the

treatment of DVT with rivaroxaban. Special Authority not approved for dabigatran for treatment of DVT or PE.

If the patient has reached his/her deductible on Pharmacare, rivaroxaban does not cost the patient any money

Otherwise, cost of rivaroxaban is ~$3/day for 20mg po daily. Cost of dabigatran is ~$3.4/day.

Rivaroxaban vs. Dabigatran No bridging with LMWH required with rivaroxaban OD vs. BID dosing Rivaroxaban is superior to warfarin in reducing

major bleeding events whereas dabigatran is non-inferior

Rivaroxaban is cheaper; rivaroxaban may be free for patients who have reached their deductible

Less renally cleared Both irreversible but rivaroxaban has shorter

half-life

Rivaroxaban vs. Apixaban No bridging needed for both drugs OD vs. BID dosing Both non-inferior to warfarin in

recurrent VTEs and VTE-related deaths

Both superior to warfarin in number of major bleeding events

Both are less renally cleared in comparison to dabigatran

Take Away Points Not all SVT are treated conservatively Remember to utilize VQ scans in those who

meet the VQ criteria Direct Factor Xa inhibitors are superior to

warfarin in reducing major bleeding risk Bridging not required for rivaroxaban or

apixaban Your patient’s rivaroxaban cost may be

covered fully in the treatment of DVT. Please use special authority.

Questions?

Thank you!