DEEP VEIN THROMBOSIS












  • Of these patients, 99% had associated distal DVT
  • Reference [7]
DVT location in 189 patients diagnosed with venography
Location of DVT % of patients
Proximal DVT 88%
Isolated distal DVT 12%

  • Reference [7]
DVT location in 166 patients with a proximal DVT diagnosed by venography
Location of DVT % of patients
Popliteal 10%
Popliteal and femoral 42%
Popliteal, femoral, and common femoral 5%
All proximal veins 35%
Common femoral +/- femoral or iliac 8%














DVT diagnostic algorithm
STEP 1 - Use Wells scoring to determine patient's risk of DVT

  • If both legs are symptomatic, use more symptomatic leg
  • Reference 4
Wells score
Finding / History Points
Active cancer (treatment ongoing, administered within previous 6 months or palliative) +1
Paralysis or recent immobilization of the lower extremity +1
Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks +1
Localized tenderness along distribution of deep vein system +1
Swelling of entire leg +1
Calf swelling ≥ 3 cm larger than that of the unaffected leg (measured 10 cm below the tibial tuberosity) +1
Pitting edema confined to affected leg +1
Dilated superficial veins on affected leg (nonvaricose) +1
Previously documented DVT +1
Alternative diagnosis at least as probable as DVT -2
STEP 2 - Determine probability of DVT

  • Reference [4]
Wells Score DVT probability
≤ 0 Low probability
1 - 2 Moderate probability
≥ 3 High probability
STEP 3 - Based on the patient's probability, do the following:

  • Reference [3,4]
Probability Testing
High probability
  • Perform ultrasound
Moderate or low probability
  • Order D-dimer
  • If D-dimer is elevated, order ultrasound
  • If D-dimer is normal, DVT unlikely [3,4]






















  • DVT considered provoked if recent surgery or transient, nonsurgical risk factor
  • ACCP does not recommend anticoagulation in certain distal DVTs (see distal DVT recs above)
  • Reference [10]
ACCP recommendations for extended anticoagulation after 3 months of anticoagulation
Provoked vs unprovoked Proximal vs distal
(see location above)
First vs second Bleeding risk
(see bleeding risk below)
Extended anticoagulation
provoked proximal and distal not specified any no
unprovoked proximal first low or moderate yes
unprovoked proximal first high no
unprovoked proximal second low or moderate yes
unprovoked proximal second high no
unprovoked distal first any no
unprovoked distal second low or moderate yes
unprovoked distal second high no
Active cancer - ACCP recommends extended anticoagulation in all patients with active cancer









  • Reference [11]
Recurrence rate in first year after treatment of initial VTE with no extended anticoagulation
Type of VTE Recurrence
Provoked by surgery 1.0%
Provoked by nonsurgical risk factor 5.8%
Unprovoked VTE 7.9%

  • Reference [25]
Cumulative recurrent VTE risk for patients who discontinued anticoagulation after a first unprovoked VTE
Time VTE (Men) VTE (Women)
2 years 18.3% 13.6%
5 years 28.6% 21.2%
10 years 41.2% 28.8%


  • Reference [27]
Cumulative recurrent VTE risk by initial VTE site for patients with first unprovoked VTE who were not anticoagulated
Time Distal DVT Proximal DVT PE
10 years 17% 37% 34%
20 years 30% 47% 44%



  • Estrogen women were taking estrogen-containing OCPs or hormone replacement therapy when their first DVT occurred
  • Five-year results were reported in a separate study [PMID 31033194]
  • References [26,28]
Risk of recurrent VTE after negative D-dimer testing
Follow-up Men Non-estrogen Women Estrogen Women
Average of 2.2 years 18.3% 11% 0%
Median of 5 years 29.7% 17% 2.3%





Estimated effect over 5 years of treatment with anticoagulation (% are absolute changes)
Low bleeding risk* Intermediate bleeding risk* High bleeding risk*
First VTE provoked by surgery Recurrent VTE reduction ↓ 2.6% ↓ 2.6% ↓ 2.6%
Major bleeding increase ↑ 2.4% ↑ 4.9% ↑ 19.6%
First VTE provoked by a nonsurgical factor / first unprovoked distal DVT Recurrent VTE reduction ↓ 13.2% ↓ 13.2% ↓ 13.2%
Major bleeding increase ↑ 2.4% ↑ 4.9% ↑ 19.6%
First unprovoked proximal DVT or PE Recurrent VTE reduction ↓ 26.4% ↓ 26.4% ↓ 26.4%
Major bleeding increase ↑ 2.4% ↑ 4.9% ↑ 19.6%
Second unprovoked VTE Recurrent VTE reduction ↓ 39.6% ↓ 39.6% ↓ 39.6%
Major bleeding increase ↑ 2.4% ↑ 4.9% ↑ 19.6%







SOME study - Screening for Occult Cancer in Unprovoked VTE, NEJM (2015) [PubMed abstract]
  • The SOME study enrolled 862 patients with a new diagnosis of first unprovoked symptomatic VTE
Main inclusion criteria
  • First unprovoked VTE (proximal DVT, PE, or both)
  • Unprovoked VTE defined as VTE occurring in the absence of known cancer, current pregnancy, thrombophilia, previous VTE, and recent immobilization
Main exclusion criteria
  • Age < 18 years
  • Weight ≥ 130 kg
  • Ulcerative colitis
  • Glaucoma
Baseline characteristics
  • Average age 53 years
  • Average weight 90 kg
  • Current or past smoker - 48%
  • Index event: DVT - 67% | PE 32% | Both - 12%
Randomized treatment groups
  • Group 1 (431 patients) - CBC; CMP; Chest X-ray; Mammography in women > 50 years; PAP in women 18 - 70 years; PSA testing in men > 40 years
  • Group 2 (423 patients) - same testing as Group 1 + CT scan of the abdomen and pelvis
  • CT scan included a virtual colonoscopy and gastroscopy, biphasic enhanced CT of the liver, parenchymal pancreatography, and uniphasic enhanced CT of the distended bladder
Primary outcome: confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
Results

Duration: 1 year
Outcome Group 1 Group 2 Comparisons
New cancer diagnosis 3.2% 4.5% p=0.28
Primary outcome 4 occult cancers were missed 5 occult cancers were missed p=1.0
Mean time to cancer diagnosis 4.2 months 4 months p=0.88
Cancer-related mortality 1.4% 0.9% p=0.75

Findings: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit.














WARFASA Study - Aspirin vs Placebo for the Secondary Prevention of VTE, NEJM (2012) [PubMed abstract]
  • The WARFASA study enrolled 402 patients with first episode of unprovoked DVT or PE
Main inclusion criteria
  • First episode of symptomatic, unprovoked proximal DVT, pulmonary embolism, or both
  • Completed anticoagulation therapy lasting 6 - 18 months
Main exclusion criteria
  • Cancer
  • Thrombophilia
  • History of cardiovascular disease requiring aspirin
  • High risk for bleeding or bleeding during anticoagulation
  • Women with VTE associated with the use of estrogen/progestin therapy
Baseline characteristics
  • Average age 62 years
  • Average BMI - 27
  • Index event: DVT ∼ 63% | PE ∼ 37%
  • Duration of anticoagulation: 6 months ∼ 34% | 12 months ∼ 55% | 18 months ∼ 10%
Randomized treatment groups
  • Group 1 (205 patients) - Aspirin 100 mg daily
  • Group 2 (197 patients) - Placebo
Primary outcome: recurrence of thromboembolism (defined as symptomatic, objectively confirmed DVT, PE, or fatal PE) over 2 years
Results

Duration: 2 years
Outcome Aspirin Placebo Comparisons
Primary outcome (% of patients/year) 6.6% 11.2% HR 0.58, 95%CI [0.36 - 0.93], p=0.02
Major bleeding or clinically relevant nonmajor bleeding 4 events 4 events HR 0.98, 95%CI [0.24 - 3.96], p=0.97
Overall mortality 6 events 5 events HR 1.04, 95%CI [0.32 - 3.42], p=0.95

Findings: Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding.
ASPIRE Study - Aspirin vs Placebo for the Secondary Prevention of VTE, NEJM (2012) [PubMed abstract]
  • The ASPIRE study enrolled 822 patients with first episode of unprovoked DVT or PE
Main inclusion criteria
  • First episode of unprovoked DVT involving the popliteal or more proximal veins or an acute pulmonary embolism
  • Completed anticoagulation therapy lasting 6 weeks to 24 months
Main exclusion criteria
  • Index VTE that occurred ≥ 2 years before enrollment
  • VTE occurred in the setting of estrogen/progestin therapy
Baseline characteristics
  • Average age 55 years
  • Index event: DVT - 57% | PE - 28% | Both - 14%
  • Duration of anticoagulation ≥ 3 months - 99% of patients
Randomized treatment groups
  • Group 1 (411 patients) - Enteric-coated aspirin 100 mg daily
  • Group 2 (411 patients) - Placebo
  • The study was originally designed to enroll 3000 patients, but was unable to achieve that number due to poor recruitment
Primary outcome: recurrence of thromboembolism (defined as symptomatic, objectively confirmed DVT, PE, or fatal PE)
Results

Duration: Median of 37.2 months
Outcome Aspirin Placebo Comparisons
Primary outcome (% of patients/year) 4.8% 6.5% HR 0.74, 95%CI [0.52 - 1.05], p=0.09
Major or clinically relevant nonmajor bleeding (% of patients/year) 1.1% 0.6% HR 1.73, 95%CI [0.72 - 4.11], p=0.22
Composite of recurrent VTE, MI, stroke, or cardiovascular death (% of patients/year) 5.2% 8.0% HR 0.66, 95%CI [0.48 - 0.92], p=0.01
  • In Group 1, 15% of patients discontinued aspirin. In Group 2, 7% of patients initiated antiplatelet or anticoagulation treatment.
  • The poor enrollment of the study left it underpowered to assess the primary outcome

Findings: In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism.
Meta-analysis of WARFASA and ASPIRE Trials, NEJM (2012) [PubMed abstract]
  • The authors of the ASPIRE study and the WARFASA study performed a pre-specified meta-analysis that combined the two studies
  • Results of the meta-analysis showed the following:
    • Aspirin reduced the relative risk of recurrent venous thromboembolism by 32% (HR 0.68, 95%CI [CI 0.51 - 0.90], p=0.007)
    • There was no significant difference between the two groups in clinically relevant bleeding. Aspirin - 2.92%, Placebo - 1.97% (HR 1.47, 95%CI [0.70 - 3.08], p=0.31) [14]
EINSTEIN CHOICE trial - Rivaroxaban vs Aspirin for Secondary Prevention of VTE, NEJM (2017) [PubMed abstract]
  • The EINSTEIN CHOICE trial enrolled 3396 patients with VTE who had completed 6 - 12 months of treatment with anticoagulation
Main inclusion criteria
  • Confirmed symptomatic PE and/or DVT treated for 6 to 12 months with anticoagulation without interruption for > 1 week
Main exclusion criteria
  • Liver disease with coagulopathy
  • CrCl < 30 ml/min
  • Indication for anticoagulant or antiplatelet therapy
  • High risk of bleeding
Baseline characteristics
  • Average age 58 years
  • Index event: DVT - 51% | PE - 33% | Both - 15%
  • Provoked VTE - 58% | Unprovoked VTE - 42%
  • Known thrombophilia - 7%
  • Previous VTE - 18%
Randomized treatment groups
  • Group 1 (1107 patients) - Rivaroxaban 20 mg once daily
  • Group 2 (1127 patients) - Rivaroxaban 10 mg once daily
  • Group 3 (1131 patients) - Aspirin 100 mg once daily
  • Study drugs were administered for up to 12 months
Primary outcome: Composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out
Results

Duration: Median of 351 days
Outcome Riv 20 mg Riv 10 mg Aspirin Comparisons
Primary outcome 1.5% 1.2% 4.4% 1 or 2 vs 3 p<0.001
Major bleeding 0.5% 0.4% 0.3% p>0.05 for all comparisons
Overall mortality 0.7% 0.2% 0.6% N/A
DVT 0.8% 0.6% 2.6% N/A
PE 0.5% 0.4% 1.7% N/A
Provoked index event (primary outcome) 1.4% 0.9% 3.6% N/A
Unprovoked index event (primary outcome) 1.8% 1.5% 5.6% N/A

Findings: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates.





Aspirin vs Rivaroxaban for VTE prophylaxis after Hip or Knee Replacement, NEJM (2018) [PubMed abstract]
  • The trial enrolled 3424 patients who were undergoing total hip or knee arthroplasty
Main inclusion criteria
  • Undergoing elective unilateral primary or revision hip or knee arthroplasty
Main exclusion criteria
  • Hip or lower limb fracture in previous 3 months
  • Metastatic cancer
Baseline characteristics
  • Average age - 63 years
  • History of VTE - 2.3%
  • Hip replacement - 1804
  • Knee replacement - 1620
Randomized treatment groups
  • Group 1 (1717 patients): Rivaroxaban 10 mg once daily for 14 days following knee replacement or 35 days following hip replacement
  • Group 2 (1707 patients): Rivaroxaban 10 mg once daily for 5 days followed by aspirin 81 mg once daily for 9 days following knee replacement or 30 days following hip replacement
Primary outcome:
  • Effectiveness - symptomatic VTE confirmed by objective testing within 90 days of randomization
  • Safety - bleeding, including major or clinically relevant nonmajor bleeding
Results

Duration: 90 days
Outcome Rivaroxaban Rivaroxaban / Aspirin Comparisons
Symptomatic VTE 0.70% 0.64% diff 0.06%, 95%CI [−0.55 to 0.66], p<0.001 for noninferiority and p=0.84 for superiority
Major bleeding 0.29% 0.47% diff 0.18%, 95%CI [−0.65 to 0.29], p=0.42

Findings: Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism