Diagnostic and Therapeutic Approach to Venous Thromboembolism Dr. Mark Choi, MD General Internal Medicine Abbotsford Regional Hospital and Cancer Centre
Jan 25, 2015
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!