PULMONARY EMBOLISM















  • Reference [4]
Symptom Percent of patients with confirmed PE
Shortness of breath 80%
Pleuritic chest pain 52%
Cough 20%
Syncope 19%
Chest pain (substernal) 12%
Hemoptysis (coughing up blood) 11%

  • Reference [4]
Physical exam finding Percent of patients with confirmed PE
Rapid respiratory rate (≥ 20/min) 70%
Rapid heart rate (≥ 100/bpm) 52%
Symptoms of DVT
(see DVT diagnosis)
20%
Cyanosis 11%
Fever (> 101.3) 7%



PE diagnostic algorithm
STEP 1 - Determine if the patient is stable
  • Unstable patients
    • Unstable patients will have signs of shock and hypotension (ex. SBP < 90 mmHg, blood pressure drop of ≥ 40 mmHg for > 15 minutes, hypoxia)
    • About 5 - 10% of PEs will present with shock or hypotension
    • These patients should proceed immediately to CT scan. If CT scan is not immediately available, they should have transesophageal echocardiography to evaluate for right ventricular strain.
    • Patients with PE who are unstable should be considered for thrombolysis or embolectomy (see other treatments below) [4]
  • Stable patients
    • Proceed to Step 2
STEP 2 - Assess patient's probability of PE using Wells score

  • Reference [4,5]
Finding / History Points
Signs and symptoms of DVT +3
Heart rate > 100 bpm +1.5
Recently immobilization or surgery (≤ 4 weeks) +1.5
Previous PE or DVT +1.5
Hemoptysis (coughing up blood) +1
Cancer +1
Pulmonary embolism more likely than alternative diagnosis +3
STEP 3 - Determine probability of PE

  • Reference [4]
Wells Score PE probability
< 2 Low probability
2 - 6 Intermediate probability
≥ 7 High probability
STEP 4 - Based on the patient's probability, do the following:

  • Reference [19]
Probability Testing
High
  • Perform CT scan
Intermediate
  • Order D-dimer
  • If D-dimer is elevated, order CT scan
  • If D-dimer is normal, PE unlikely [4, 5]
Low
  • If patient meets all Pulmonary embolism rule-out criteria (see below), do not order D-dimer or imaging studies (probability of PE < 1%)
  • If patient does not meet all Rule-Out Criteria, order D-dimer [19]
Pulmonary embolism rule-out criteria
  • The PE rule-out criteria is a set of 8 criteria that if all are met, the risk of PE is very low and testing for PE (e.g. D-dimer, imaging) is not indicated
  • Use of the criteria has been validated in trials [PMID 29450523]

  • Reference [19]
Pulmonary Embolism Rule-Out Criteria
Age < 50 years
Initial heart rate < 100 beats/min
Initial oxygen saturation > 94% on room air
No unilateral leg swelling
No hemoptysis
No surgery or trauma within 4 weeks
No history of VTE
No estrogen use























  • Provoked - recent surgery or transient, nonsurgical risk factor
  • Reference 7
Provoked vs unprovoked First vs second Bleeding risk
(see bleeding risk below)
Extended anticoagulation recommended
provoked not specified any no
unprovoked first low or moderate yes
unprovoked first high no
unprovoked second low or moderate yes
unprovoked second high no
Active cancer - ACCP recommends extended anticoagulation in all patients with active cancer


Overview
  • For patients with a first unprovoked PE, the risks of extended anticoagulation (bleeding) have to be weighed against the benefits (lower risk of recurrence)
  • One large randomized trial has evaluated the risk/benefit ratio of extended anticoagulation in patients with first unprovoked PE
PADIS-PE trial - Extended Anticoagulation vs None after First Unprovoked PE, JAMA (2015) [PubMed abstract]
  • The PADIS-PE trial enrolled 374 patients with a first unprovoked PE that had been treated for 6 uninterrupted months with a vitamin K antagonist
Main inclusion criteria
  • First symptomatic, unprovoked PE (unprovoked PE defined as objectively confirmed PE occurring in the absence of any major reversible risk factor for VTE within 3 months before diagnosis, including surgery with locoregional or general anesthesia lasting more than 30 minutes, trauma with or without plaster cast of the lower limbs, and bed rest for more than 72 hours, and in the absence of active cancer or cancer resolved within the 2 years prior to diagnosis)
Main exclusion criteria
  • Previous VTE (proximal DVT or PE)
  • Bleeding during the initial 6-month anticoagulation
  • Known hypercoagulable disorder
  • Increased bleeding risk (e.g. active gastric ulcer, recent hemorrhagic stroke)
  • Platelet count < 100,000/mm³
Baseline characteristics
  • Average age 58 years
  • Previous distal DVT or superficial vein thrombosis ∼8%
  • PE treatment prior to enrollment: Warfarin ∼67% | Other VKA ∼33%
  • ACCP bleeding risk category: - Low 24% | Moderate 32% | High 43%
Randomized treatment groups
  • Group 1 (184 patients) - Warfarin for 18 months (target INR 2 - 3)
  • Group 2 (187 patients) - Placebo for 18 months
Primary outcome: composite of symptomatic recurrent VTE (objectively confirmed nonfatal symptomatic PE or proximal DVT or fatal venous thromboembolism) and nonfatal or fatal major bleeding up to 18 months
Results

Duration: 18 months
Outcome Warfarin Placebo Comparisons
Primary outcome 3.3% 13.5% HR 0.22, 95%CI [0.09 - 0.55], p=0.001
Recurrent VTE 1.7% 13.5% HR 0.15, 95%CI [0.05 - 0.43], p<0.001
Major bleeding 2.2% 0.5% HR 3.96, 95%CI [0.44 - 35.89], p=0.22
  • After the 18 month treatment period, all patients were followed for a median of 24 months without anticoagulant therapy. The risk for the composite outcome was not significantly different at the end of this period (Warfarin - 20.8%, Placebo - 24%, p=0.22)
  • In the warfarin group, the INR was in the therapeutic range (2 - 3) for 70% of the time

Findings: Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy.
Summary
  • The PADIS-PE study showed that the benefits of extended anticoagulation in patients with first unprovoked PE outweigh the potential risks. It's also important to note that 43% of the subjects were categorized at baseline as "high bleeding risk" by the ACCP bleeding risk criteria. According to the latest ACCP guidelines, extended anticoagulation would not have been recommended for these patients.
  • During the 24 month post-treatment phase, risk of VTE in the warfarin group returned to that of the placebo group. This shows that extending initial anticoagulation by 18 months does not appear to lower future risk of VTE.







  • Reference [6]
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 [23]
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 [24]
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%




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%






Overview
  • Up to 10% of patients with an unprovoked venous thromboembolism (VTE) are diagnosed with cancer within a year following their event
  • This observation causes some providers to order extensive cancer workups in patients with unprovoked venous thromboembolism. Whether this practice is prudent is a matter of debate. [17,18]
  • A study published in 2015 in the NEJM compared the effectiveness of two cancer screening approaches in patients with unprovoked venous thromboembolism
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 Screening Screening + CT 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.
Summary
  • The SOME study found no benefit of adding an abdominal and pelvic CT to standard screening in patients with unprovoked VTE
  • It's unclear if an unprovoked VTE is a marker of increased cancer risk. In order to evaluate this, a group of patients with unprovoked VTE would have to be compared with a matched control group that underwent all of the same testing. No such study has been performed. The high incidence of cancer in patients diagnosed with VTE may be a product of surveillance bias as opposed to an association of VTE with cancer risk. Some studies have found that the risk of cancer following VTE returns to normal after 6 months. This finding tends to argue against VTE being a marker of increased cancer risk. [18]











Secondary prevention of VTE
  • Daily aspirin has been evaluated in the secondary prevention of VTE in several studies
  • The WARFASA and ASPIRE studies compared aspirin to placebo in patients with a first episode of unprovoked VTE
  • The EINSTEIN CHOICE study compared aspirin to two different doses of rivaroxaban in patients with provoked and unprovoked VTE
  • All three studies are presented below. Results from a meta-analysis that combined the WARFASA and ASPIRE studies are also presented.
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 + 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) [12]
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.
Summary
  • The ASPIRE study did not show a statistically significant effect of aspirin in preventing recurrent VTE, although there was a trend towards significance with a p-value of 0.09. The study had poor enrollment and was underpowered.
  • The WARFASA study, a much smaller study, found a significant effect with aspirin after two years of follow-up
  • The meta-analysis that combined the two studies found that aspirin reduced the relative risk of VTE by 32%
  • Not surprisingly, the EINSTEIN-CHOICE trial found rivaroxaban to be superior to aspirin for preventing VTE. Also of note, the 10 mg dose of rivaroxaban was as effective as the 20 mg dose.
  • Across all 3 studies, the risk of recurrent VTE with daily aspirin was between 4.4 - 6.6% per year. The risk for patients in the EINSTEIN CHOICE trial with a provoked VTE as the index event was slightly lower at 3.6%. In the placebo arms of WARFASA and ASPIRE, the risk of recurrent VTE was 11.2% and 6.5%, respectively.
  • Collectively, these three trials help quantify the risk of recurrent VTE for patients who choose to take aspirin over anticoagulation



Primary prevention after TKA / THA
  • Patients who undergo total hip or knee replacement surgery are at high risk for VTE in the immediate postoperative period
  • Anticoagulants like low-molecular weight heparins and Factor Xa inhibitors are often prescribed for 15 - 35 days after surgery to prevent VTE
  • A study published in the NEJM in 2018 compared rivaroxaban only to 5 days of rivaroxaban followed by aspirin for VTE prevention in patients undergoing joint replacement surgery. The study is summarized below.
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
Summary
  • Five days of anticoagulation followed by daily aspirin appears to be a safe and effective alternative to continuous anticoagulation for VTE prophylaxis after joint replacement surgery
  • A previous study that compared aspirin to dalteparin came to similar conclusions [PMID 23732713]