American College of Chest Physicians Guideline on Antithrombotic Therapy for VTE Disease
SUMMARY:
The decision whether to prescribe anticoagulation (AC) for deep vein thrombosis (DVT) or pulmonary embolism (PE), and for what duration, is a highly individualized one that must take into account several clinical variables as well as patient preferences. Recommendations for AC are tailored based on a patient’s bleeding risk profile, characteristics of DVT (proximal vs. distal) and the clinical context in which VTE has occurred (provoked vs. unprovoked, association with active cancer). The American College of Chest Physicians offers a comprehensive evidence-based guideline on how and when to treat VTE with anticoagulation.
Anticoagulation Choices
No Active Cancer
Novel oral anticoagulants (NOAC) preferred over warfarin or low-molecular-weight heparin (LMWH)
NOACs (equivalent efficacy for treatment of VTE): dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa)
Dabigatran and edoxaban require initial parenteral therapy (unfractionated or LMWH) | Rivaroxaban and apixaban do not
If NOAC contraindicated: Use warfarin
With Active Cancer
LMWH
Inferior vena cava (IVC) filter
Reserved for patients with proximal DVT/PE who have an absolute contraindication to anticoagulation such as active bleeding
Not recommended in combination with AC
Proximal DVT or PE
Provoked by surgery or a “nonsurgical transient risk factor” (e.g. pregnancy hormone therapy, long-distance air travel, leg injury)
3 months AC
Duration is based on evidence that provoked VTE has a lower risk of recurrence
Unprovoked (no surgery or identifiable transient risk factor)
While hereditary thrombophilia is associated with an increased VTE risk, there is little clinical benefit of testing for this condition, as its utility in decision making regarding anticoagulation is low
Without Active Cancer
Low or moderate bleeding risk
“At least” 3 months vs extended (no stop date) AC
Decision to continue AC beyond 3 months influenced by patient sex and D-dimer (measured 1 month after stopping AC)
Men have 75% higher risk of recurrence than women
Positive D-dimer: Double risk of recurrence
High bleeding risk
3 months AC
“After 3 months of treatment, patients with unprovoked DVT of the leg or PE should be evaluated for the risk-benefit ratio of extended therapy.”
With Active Cancer
Extended AC regardless of bleeding risk
“In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals”
If decision is made to stop AC for unprovoked VTE,
“suggest” aspirin to prevent recurrence | Not as effective as AC
Isolated Distal DVT
“It is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants”
Initiate AC (provoked or unprovoked)
3 months AC or
Serial US imaging for 2 weeks if no severe symptoms or risk factors for extension
Risk factors for extension include
Positive D-dimer | Extensive (>5 cm) thrombus | Thrombus close to proximal veins | No reversible provoking factor | Active cancer | Prior VTE | Inpatient status
Initiate AC if
Thrombus has extended on repeat imaging (even if it remains isolated to distal veins)
Severe symptoms or risk factors for extension are present
Administer AC according to same rules as for proximal DVT
KEY POINTS:
Recurrent VTE
Patient already on warfarin (with therapeutic INR) or NOAC with good compliance
Switch to LMWH for at least 1 month
Already on LMWH: Increase dose by 1/4 to 1/3
Risk of recurrent VTE
Low risk: VTE is provoked by surgery
Intermediate risk: Provoked by a non-surgical risk factor
High risk: Unprovoked
Special Considerations
Upper Extremity DVT
Commonly provoked by central venous catheter
Axillary or more proximal veins
3 months AC
Consider thrombolysis for patient with
Severe symptoms lasting <14 days | Thrombus involving most of subclavian and axillary veins | Good functional status and life expectancy | Low bleeding risk
Subsegmental PE And No Proximal DVT
Low risk of recurrence: Clinical surveillance
High risk of recurrence: AC
Hemodynamically significant PE (causing hypotension)
Low or moderate bleeding risk: systemic thrombolysis
High bleeding risk, failed thrombolysis, or shock: catheter-directed thrombectomy
Anticoagulant Options for Acute VTE
Apixaban
10 mg oral twice daily for 7 days
5 mg oral twice daily
Consider 2.5 mg twice daily beyond 6 months
Rivaroxaban
15 mg oral twice daily for 21 days
20 mg once daily
Consider 10 mg daily beyond 6 months
Warfarin
Start a parenteral anticoagulant and warfarin simultaneously
Continue LMWH for a minimum of 5 days and until the INR has reached ≥2 on 2 consecutive days then stop the parenteral anticoagulant and continue warfarin alone
Adjust warfarin dose to target INR 2.0 to 3.0
LMWH
Dalteparin (CrCl ≥ 30 mL/min)
200 units/kg subcutaneously once daily or 100 units/kg twice daily
Enoxaparin
CrCl ≥ 30 mL/min: 1.5 mg/kg subcutaneously once daily or 1 mg/kg twice daily
CrCl ≤ 30 mL/min: 1 mg/kg subcutaneously once daily
The CMQCC Toolkit: Pregnancy Related Risk Factors & Thrombophilia Defined
SUMMARY:
The CMQCC Task Force has released guidance on the prevention of PE and DVT in pregnancy. The document also helps clarify terminology to provide clarity when performing risk assessment at various time points in pregnancy (see ‘Related ObG Topics’ below). In addition, the CMQCC Task Force provides the anti-coagulation regimens recommended by ACOG.
Risk Factors
FAMILY HISTORY of VTE
VTE occurring in a first-degree relative prior to age 50
HIGH RISK THROMBOPHILIA
Antithrombin III deficiency
Antiphospholipid syndrome (APS)
Requires at least one clinical and one laboratory criteria be met
Factor V Leiden or Prothrombin pathogenic variant
Homozygosity or compound heterozygosity
LOW RISK THROMBOPHILIA
Factor V Leiden or Prothrombin pathogenic variant
Heterozygote state
Protein C or S deficiency
Anticoagulation Regimens (ACOG)
LMWH – PROPHYLACTIC DOSE
Enoxaparin, 40 mg SC once daily
Dalteparin, 5,000 units SC once daily
Tinzaparin, 4,5000 units SC once daily
Nadroparin, 2,850 units SC once daily
LMWH – INTERMEDIATE DOSE
Enoxaparin, 40 mg SC every 12 hours
Dateparin, 5,000 units SC every 12 hours
LMWH – ADJUSTED DOSE (THERAPEUTIC)
Enoxaparin, 1mg/kg SC every 12 hours
Dalteparin, 200 units/kg SC once daily
Tinzaparin, 175 units/kg SC once daily
Dalteparin, 100 units/kg every 12 hours
UFH – PROPHYLACTIC
UFH, 5,000-7,500 units SC every 12 hours in first trimester
UFH, 7,500-10,000 units SC every 12 hours in the second trimester
UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated
UFH – ADJUSTED DOSE (THERAPEUTIC)
UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5-2.5) 6 hours after the injection
POSTPARTUM ANTICOAGULATION
Prophylactic, intermediate or adjusted dose LMWH for 6-8 weeks as indicated
Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation and patient preference
SURVEILLANCE
Clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep vein thrombosis or pulmonary embolism
VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility
Notes:
Anti-Xa level testing is available to monitor activity of LMWH agents
CMQCC defines ‘LMWH therapeutic dose’ as enoxaparin, 1mg/kg SC every 12 hours, adjusted to target Xa 0.6-1.0 units/mL 4-6 hours after injection with acute VTE
aPTT testing is used to determine UFH dosing, not LMWH activity
Anti-Xa level testing is not currently mandated due to cost, inconvenience and lack of high quality data
Dose adjustment may be considered with extremes of body weight (< 50 kg or > 90 kg)
Consultation and ongoing collaboration with Anesthesia is strongly recommended
The CMQCC Toolkit: Venous Thromboembolism and Antepartum Admission (Non-Delivery)
SUMMARY:
The Joint Commission has recommended guidance for non-pregnant patients who are admitted to hospital. However, due to lack of data, despite known increased risk, pregnant women were not included in this directive. The CMQCC Maternal VTE task force provides recommendations to address this gap. Pregnant women who are admitted to hospital should be encouraged to
Maintain full ambulation
Risks of activity restriction and bedrest are proven and include VTE, bone loss, poor maternal weight gain and rapid deconditioning
There is also evidence that there may be risk of anxiety, and peri and postpartum depression
There is no evidence that bedrest improves outcomes for multiple gestations, preterm labor, hypertensive disease of pregnancy or IUGR
Ensure hydration
Prophylaxis
Mechanical: Utilize mechanical prophylaxis (knee length sequential compression devices) while in bed
Pharmacologic: Based on data that length of stay ≥3 days is associated with high risk for VTE, the toolkit document states
The CMQCC Maternal VTE Task Force supports NPMS and RCOG recommendations for pharmacological thromboprophylaxis for all antepartum patients hospitalized for ≥ 72 hours who are not at high risk for bleeding or imminent delivery.
Antepartum Hospital Admission VTE Risk Assessment
LOW RISK
All patients not in high risk category with anticipated admission <72 hours
Treatment
MECHANICAL PROPHYLAXIS (reassess at 72 hours)
MEDIUM RISK
All patients admitted not in high risk category with anticipated or actual length of stay >72 hours
Treatment
MECHANICAL PROPHYLAXIS and PROPHYLACTIC DOSE LMWH OR UFH
HIGH RISK
High risk thrombophilia
Low risk thrombophilia and family history of VTE
Antiphospholipid Syndrome (APS), even without prior VTE regardless of family history
Prior provoked, idiopathic, or estrogen related VTE (i.e., personal history of any VTE)
Patients already receiving LMWH or UFH as outpatient for multiple prior VTE episodes or for prior VTE with high risk thrombophilia or APS
Treatment
(1) MECHANICAL PROPHYLAXIS + PROPHYLACTIC DOSE LMWH/UFH or
(2) MECHANICAL PROPHYLAXIS + PROPHYLACTIC or THERAPEUTIC DOSE LMWH/UFH (consistent with antepartum dosing)
Notes:
Mechanical prophylaxis should be placed on admission and continued through discharge
Prophylactic-dose LMWH or UFH should be determined in collaboration with anesthesia
Obtain anesthesia consultation at the time of antepartum admission for all patients who are potential candidates for pharmacologic prophylaxis
Obstetricians and anesthesiologists should maintain ongoing and close communication, ensuring that all providers are involved in the anticoagulation plan
Multidisciplinary approach will address
Neuraxial anesthesia
Dose adjustments of pharmacologic prophylaxis
Coagulation testing when indicated
KEY POINTS:
Patient at high risk VTE but also at risk for delivery or bleeding
Mechanical prophylaxis or low dose UFH 5000 units subcutaneous every 12 hours may be utilized
If pharmacologic prophylaxis deemed appropriate by multidisciplinary team, low dose UFH 5000 units subcutaneous every 12 hours is preferred due to
Rapid reversal, shorter half-life, and facilitation of regional anesthesia
Patient at high risk for imminent delivery and/or requiring neuraxial anesthesia
Hold pharmacological prophylaxis and utilize mechanical prophylaxis due to risk benefit analysis
Competing risks (DVT vs bleeding) underlie the CMQCC Task Force’s strong recommendation to obtain anesthesia input prior to a decision to initiate pharmacologic prophylaxis
Definitions – Risk Factors
FAMILY HISTORY of VTE
VTE occurring in a first-degree relative prior to age 50
HIGH RISK THROMBOPHILIA
Antithrombin III deficiency
Antiphospholipid syndrome (APS)
Requires at least one clinical and one laboratory criteria be met
Factor V Leiden or Prothrombin pathogenic variant
Homozygosity or compound heterozygosity
LOW RISK THROMBOPHILIA
Factor V Leiden or Prothrombin pathogenic variant
Heterozygote state
Protein C or S deficiency
Definitions – Anticoagulation Regimens (ACOG)
LMWH – PROPHYLACTIC
Enoxaparin, 40 mg SC once daily
Dalteparin, 5,000 units SC once daily
Tinzaparin, 4,500 units SC once daily
Nadroparin, 2,850 units SC once daily
LMWH-INTERMEDIATE DOSE
Enoxaparin, 40 mg SC every 12 hours
Dalteparin, 5,000 units SC every 12 hours
LMWH – ADJUSTED DOSE (THERAPEUTIC)
Enoxaparin, 1mg/kg SC every 12 hours
Dalteparin, 200 units/kg SC once daily
Tinzaparin, 175 units/kg SC once daily
Dalteparin, 100 units/kg SC every 12 hours
UFH – PROPHYLACTIC
UFH, 5,000 to 7,500 units SC every 12 hours in first trimester
UFH, 7,500 to 10,000 units SC every 12 hours in the second trimester
UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated
UFH – ADJUSTED DOSE (THERAPEUTIC)
UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5 to 2.5 x control) 6 hours after the injection
POSTPARTUM ANTICOAGULATION
Prophylactic, intermediate or adjusted dose LMWH for 6 to 8 weeks as indicated
Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation and patient preference
SURVEILLANCE
Clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep vein thrombosis or pulmonary embolism
VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility
Notes:
Anti-Xa level testing is available to monitor activity of LMWH agents
CMQCC defines ‘LMWH therapeutic dose’ as enoxaparin, 1mg/kg SC every 12 hours, adjusted to target Xa 0.6-1.0 units/mL 4-6 hours after injection with acute VTE
aPTT testing is used to determine UFH dosing, not LMWH activity
Anti-Xa level testing is not currently mandated due to cost, inconvenience and lack of high quality data
Dose adjustment may be considered with extremes of body weight (<50 kg or >90 kg)
Consultation and ongoing collaboration with Anesthesia is strongly recommended
Results from the PROPER Trial: What are the Pulmonary Embolism Rule-Out Criteria (PERC) and Do They Really Work?
BACKGROUND AND PURPOSE:
The Pulmonary Embolism Rule-Out Criteria (PERC), an 8-item set of clinical criteria that serves as a predictive tool, has not been evaluated using a randomized trial (RCT)
Each PERC criteria is scores as ‘0’ (no) or ‘+1’ (yes) and a 0 score indicates no further work-up is needed, with a <2% chance of PE
Arterial oxygen saturation (Sp02) of ≤94%
Pulse rate of at least 100/min
Patient age of 50 years or older
Unilateral leg swelling
Hemoptysis
Recent trauma or surgery
Prior PE or deep venous thrombosis (DVT)
Exogenous estrogen use
Freund et al. (JAMA, 2018) aimed to validate the safety of the PERC-based strategy to exclude PE
METHODS:
A noninferiority, crossover cluster randomized controlled trial
14 EDs in France were involved for two 6-month periods separated by a 2-month washout period
Patients who came to the ED with a suspicion of PE were eligible
Inclusion criteria included
new-onset presence or worsening of shortness of breath or chest pain
Low probability of PE (clinician’s pre-test probability is <15%), based on physicians unstructured impression of risk (low, moderate, or high)
Evidence that unstructured ‘gestalt’ performs as well as structured assessment
Each center was randomized to determine sequence of intervention periods
During the PERC period, the diagnosis of PE was excluded with a PERC score of 0, with no further follow up
During the non-PERC period, usual diagnostic strategy was followed for low level of suspicion for PE
D-dimer testing
If D-dimer testing is positive, computed tomographic pulmonary angiography (CTPA) was performed
If both negative, PE was ruled out and no further follow-up
Primary outcome
Percentage of failure of the diagnostic strategy
Secondary outcomes
Rate of CTPA use
Median length of stay in the emergency department
Rate of hospital admission
RESULTS:
1916 patients were cluster-randomized (mean age 44 years, 980 [51%] women)
962 were assigned to the PERC group
954 were assigned to the control group
A total of 1,749 patients completed the trial
A PE was diagnosed at initial presentation in
26 (2.7%) of patients in the control group vs 14 (1.5%) in the PERC group
Mean difference, 1.3% (95% CI, −0.1% to 2.7%; P = .052)
Primary outcome: One symptomatic PE (0.1%) at 3 months was diagnosed during follow-up in the PERC group vs none in the control group
The proportion of patients undergoing CTPA in the PERC group vs control group was 13% vs 23%
Mean difference, 9.7% (95% CI, 6.1% to 13.2% P < .001)
In the PERC group
Median length of emergency department stay rates were significantly reduced
Mean reduction, 36 minutes (95% CI, 4 – 68)
Hospital admission rates were significantly reduced (13% vs 16%)
Mean difference, 3.3% (95% CI, 0.1% to 6.6%)
CONCLUSION:
Among low-risk patients for PE, using the PERC strategy did not result in an inferior rate of thromboembolic events over 3 months
Authors point out limitations of this study, including low initial prevalence of PE at 2.7% and may be explained by low average age
This study supports the use of PERC for very low-risk patients presenting at the emergency department
NOTE: PERC HAS NOT BEEN VALIDATED IN PREGNANCY OR POSTPARTUM
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