Risk Stratification

To improve upon the poor sensitivity and specificity of clinical examination findings, several scoring systems have been developed. Despite these objective analysis tools, 1 meta-analysis demonstrated that nonformal physician judgment was comparable to the validated scoring systems.

The Wells Scoring System

Developed in 1995, the Wells score ( Table 3 ) is the most widely used clinical decision instrument (CDI) for the diagnosis of DVT. The CDI risk stratifies patients into low, intermediate, or high risk for DVT based upon a point system that identifies risk factors and has been further developed to dichotomize patients into high and low probability categories. The interobserver reliability of the Wells score is excellent (kappa 0.85), with the most variability seen in the element of the score that considers the likelihood of an alternative diagnosis. Currently, the Wells score is recommended for use in practice in order to dichotomize or trichotomize patients into risk categories, and both methods have been independently validated.

In the original, 3-part risk stratification assessment, a Wells score (see Table 3 ) indicates levels of risk and includes low (Wells score 0 or less), moderate (Wells score 1–2), and high pretest probability (Wells score 3 or more) categories.

A 2-level risk assessment is also valid and combines the moderate- and higher-risk patients into one category. Low-risk (<2 points) and combined intermediate/high-risk (2 or more points) categories are thus created.

Both the 2-level and 3-level risk stratification techniques are used in clinical practice with adjunctive d-dimer and duplex ultrasound scanning to evaluate for DVT. A 2003 clinical policy recommendation from the American College of Emergency Physicians supports the use of DVT risk stratification using the Wells criteria along with d-dimer testing to safely exclude DVT (Level B recommendation).

D-dimer

D-dimer is a molecular marker that results from the dissolution of cross-linked fibrin. It is often elevated in thrombotic conditions; however, it may also be elevated in nonthrombotic conditions including pregnancy, malignancy, trauma, infection, and inflammatory conditions and is therefore not a specific marker for DVT. Multiple assays are available, with the enzyme linked immunosorbent assay (ELISA) possessing the highest sensitivity (94%). The current recommended testing strategy for first-time DVT includes assessment of pretest probability combined with high sensitivity d-dimer testing and compression ultrasound assessment.

In the dichotomized risk stratification approach, patients in the low category can safely undergo d-dimer testing, and if negative, the diagnosis of DVT can be reasonably excluded. If the d-dimer level is elevated, or if the pretest probability of DVT is intermediate or high based on the CDI, a duplex of the lower extremity should be performed.

In the trichotomized version, low-probability patients (Wells score 0 or less), should be offered the use of d-dimer, or proximal vein ultrasound. In moderate-probability patients (Wells score 1–2), highly sensitive d-dimer, proximal-vein ultrasound, or whole-leg ultrasound is favored over other modalities. In low- and moderate-risk patients, if d-dimer is negative, no further testing is warranted, while a positive d-dimer testing prompts compression ultrasound, but does not necessitate treatment. In high pretest probability patients, d-dimer testing should not be utilized, and one should proceed with duplex ultrasound of the extremity to evaluate for DVT. In addition, in a patient with a moderate or high pretest probability, if compression ultrasound is utilized and is initially negative, repeat testing with compression ultrasound or a moderate or high sensitivity d-dimer is recommended at 1 week follow-up. In cases where a patient has high pretest probability and there is no immediate access to utrasound, a single dose of low molecular weight heparin and a return visit within 12 hours for planned ultrasound are reasonable.

Testing for recurrent DVT is controversial, but recommendations favor the same modalities as for primary DVT assessment. Repeat duplex testing is warranted if d-dimer is positive but initial duplex is negative.

Age-Adjusted D-dimer

Increased age has the propensity to increase d-dimer values and may therefore decrease the diagnostic accuracy and specificity of the d-dimer. A 2014 systematic review found that age-adjusted (age × 10 μg per liter as the upper limit of normal) d-dimer values in older, nonhigh-risk patients increased the specificity and did not significantly decrease the sensitivity of the study. It is important to note that this was a derivation study, not a validation study, and to date the results have not undergone validation. Although not specifically evaluating the age-adjusted D-dimer on DVT, the ADJUST-PE trial did validate age-adjusted D-dimer for use in the evaluation of acute PE.

Pregnancy Adjusted D-dimer

Data have shown a consistent elevation in d-dimer levels as pregnancy progresses. This would serve to reduce the specificity of the d-dimer test, prompting unnecessary further evaluation. In 1 small study of asymptomatic women, none of the women had a d-dimer value less than the traditional cutoff value of 0.50 mg/L in the third trimester. The authors advocate for a prospective validation of cutoff values at 0.750, 1.0, and 1.5 mg/L for the first, second, and third trimesters, respectively. A small trial prospectively validated 3 d-dimer cutoff values at 286, 457, and 644 ng/mL in the first, second, and third trimesters, respectively and found 100% sensitivity for the adjusted values. The authors note their trial should be viewed as a pilot study and advocate for additional, larger studies.

Ultrasound

Duplex ultrasound imaging, which includes B-mode imaging of veins as well as pulsed Doppler flow assessment, can evaluate for DVT in the proximal veins with specificity of 94% and sensitivity of 90%. A meta-analysis pooled 7 studies and demonstrated a 0.57% 3-month rate of VTE after single negative LE compression ultrasound. Duplex imaging modalities may include proximal-vein-only methods or whole leg scanning. Positive compression ultrasound of the lower extremity is sufficient to warrant treatment, and venography is not recommended for confirmation. Although venography remains an option, it may be associated with decreased availability, increased discomfort, and more complications, but it has a lower false-positive rate. A 2003 clinical policy recommendation from ACEP supports (level B evidence) the use of venous ultrasonography to safely exclude all proximal and symptomatic distal DVT. Serial ultrasounds are recommended for high-probability cases with negative initial imaging.

Ultrasound Sites

A 2014 study identified 362 individuals with DVT on compression ultrasound, of whom 6.3% had findings of isolated thrombi in proximal veins. The study authors used the data to support the recommendation of the addition of femoral and deep femoral vein evaluation to standard compression ultrasound of the common femoral and popliteal veins. In agreement with this are the 2015 guidelines from the American Institute of Ultrasound in Medicine (AIUM), which recommend :

“The fullest visualized extent of the common femoral, femoral, and popliteal veins must be imaged using an optimal gray scale compression technique. The popliteal vein is examined distally to the tibioperoneal trunk. The proximal deep femoral and proximal great saphenous veins should also be examined. Venous compression is applied every 2 cm or less in the transverse (short axis) plane with adequate pressure on the skin to completely obliterate the normal vein lumen.”

In addition, focal symptoms require individualized assessment.

For a normal examination, the minimum assessment and imaging documentation should include gray scale images with and without compression of the

• •
  

  Common femoral vein

  
  
• •
  

  Junction of the common femoral vein with the great saphenous vein

  
  
• •
  

  Proximal deep femoral vein separately or along with the proximal femoral vein

  
  
• •
  

  Proximal femoral vein

  
  
• •
  

  Distal femoral vein

  
  
• •
  

  Popliteal vein

In addition, color spectral Doppler waveforms from the long axis should be recorded at these levels :

• •
  

  Right common femoral or external iliac vein

  
  
• •
  

  Left common femoral or external iliac vein

  
  
• •
  

  Popliteal vein on symptomatic side or on both sides if the examination is bilateral

Abnormal examination findings require documentation and imaging of the abnormal finding.

For upper extremity assessment, the 2015 AIUM guidelines recommend that gray scale images or cine loops should be recorded without and with compression at each of the following levels :

• •
  

  Internal jugular vein

  
  
• •
  

  Peripheral subclavian vein

  
  
• •
  

  Axillary vein

  
  
• •
  

  Brachial vein in the upper arm

  
  
• •
  

  Cephalic vein in the upper arm

  
  
• •
  

  Basilic vein in the upper arm

  
  
• •
  

  Focal symptomatic areas, if present

Color and spectral Doppler images are recorded at each of the following levels using the appropriate color technique to show filling of the normal venous lumen:

• •
  

  Internal jugular vein

  
  
• •
  

  Subclavian vein

  
  
• •
  

  Axillary vein

If seen, the innominate vein should be recorded with color Doppler imaging.

At a minimum, both the right and left subclavian venous spectral Doppler waveforms should be recorded to evaluate for asymmetry or loss of cardiovascular pulsatility and respiratory phasicity.

Emergency Department Physician-Performed Imaging

A 2013 meta-analysis of 16 studies that assessed the diagnostic accuracy of emergency department physician lower extremity ultrasound for DVT demonstrated a kappa value of 0.83 between investigators, with a mean sensitivity of 96.5%. In the studies analyzed, there was high variability in training among emergency department physicians and variable study type (whole leg, 2 point, 3 point). Additional studies regarding emergency department physician DVT diagnoses have been conducted and have demonstrated highly variable results (sensitivity from 66% to 100%) but were subject to poor study methods. Overall, the studies seem to demonstrate that bedside performance of ultrasound for the evaluation of LEDVT by emergency department physicians is reasonable, but perhaps dependent upon experience and level of training.

Upper Extremity Deep Venous Thrombosis

Only about 50% of clinical investigations identify DVT in patients with suspected UEDVT. Contrast venography is the gold standard but invasive and requires contrast use. Ultrasound is 82% to 97% sensitive and 82% to 96% specific, and benefits from portability and lack of radiation use. Recommendations for the evaluation of UEDVT begin with risk stratification of patients into high or low probability. Both groups should begin their evaluation with color flow duplex ultrasonography. If UEDVT is found on ultrasound, treatment should be initiated. In low-risk patients in whom ultrasound is negative, serial ultrasound can be considered, or the evaluation can be stopped. In high-risk patients, contrast venography is recommended for further evaluation.

The approach to evaluation for LEDVT is summarized in Fig. 1 .

The two-tiered algorithmic approach to diagnosing DVT.

Isolated Distal Calf Deep Venous Thrombosis

Isolated distal calf VTE is special, as these cases may not progress to proximal DVT or PE. Authors suggest that all proximal LEDVT be treated and that calf vein DVT should either be treated empirically or followed with serial ultrasound to devaluate for proximal progression. Some authors recommend acute isolated DVT without severe symptoms or risks for progression be followed with serial ultrasound rather than anticoagulation, while those patients with severe symptoms or high risk for progression be treated with anticoagulation. Shared decision-making plays a large role in the decision to treat or perform serial imaging in isolated distal DVT, as patient preference may affect adherence to the treatment plan.

The remaining discussion of therapies reflects the treatment of proximal LEDVT.

Compression Stockings

Graded compression elastic stockings utilized for 2 years have demonstrated no decreased risk of recurrence of DVT, but did reduce the risk of post-thrombotic syndrome (PTS) at 5 years. In patients with acute DVT of the leg, the CHEST guidelines suggest not using compression stockings routinely to prevent PTS. This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justified. No specific compression value is mentioned by the authors, and reference is only made to graded compression stockings.

Inferior Vena Cava Filters

In patients with acute DVT or PE who are treated with anticoagulants, the routine use of inferior vena cava (IVC) filters is not recommended. Although early embolism was reduced by filter placement in one study, the effect was transient, and data at 2 years indicated no significant reduction in mortality or recurrent symptomatic PE. In fact, another study showed increased risk of subsequent DVT at 2-year follow-up after IVC filter placement. IVC filters might be considered in patients who have acute DVT and suffer complications necessitating cessation of anticoagulation, and in those who have failed multiple forms of anticoagulation, including vitamin K antagonists (VKAs) at both the traditional international normalized ratio (INR) of 2.0 to 3.0, as well as an elevated INR of 3.0 to 4.0, and other therapies including low molecular weight heparin (LMWH) or novel oral anticoagulants (NOACs).

Aspirin

Aspirin therapy is not considered an adequate alternative to anticoagulation for treatment of DVT or PE. However, after completion of traditional therapy, aspirin may be an effective measure to prevent recurrence. The WARFASA and ASPIRE studies both evaluated ASA versus placebo in patients with unprovoked (noncancer- and nonimmobility-related VTE) after completion of traditional treatment for VTE. Both studies demonstrated reduced rates of VTE in the aspirin groups. Multiple studies of varying design, including 2 meta-analyses, have demonstrated reductions in VTE among patients on ASA or placebo for cardiovascular risk control (primary prevention). Pitfalls of studies related to the primary prevention of VTE with aspirin are largely related to VTE prevention being a secondary outcome or the result of post-hoc analysis. In none of these studies was prevention of PE by ASA a primary end point. Other large, population-based observational studies have failed to demonstrate an effect on VTE prevention by ASA.

Given the previously mentioned data, the risks and benefits of aspirin for prevention of recurrent DVT should be considered upon cessation of traditional anticoagulation. Although the data are not conclusive, aspirin therapy for secondary prevention of DVT seems a reasonable and probably effective measure, and should be considered and weighed against the risk of bleeding in the appropriate patient. In those patients with unprovoked DVT and low risk of bleeding, and in whom cessation of therapy is planned, the CHEST guidelines recommend aspirin therapy, as long as there is no contraindication to such therapy. Additionally, the use of aspirin for other primary or secondary prevention purposes (eg, stroke) should be assessed.

Aspirin has also been studied for primary prevention of VTE after orthopedic surgery, with conflicting results. The American Academy of Orthopedic Surgeons, in a 2009 statement, recommended primary prevention of VTE with ASA, based on the Pulmonary Embolism Prevention Study. CHEST recommendations now recommend ASA therapy as an alternative therapy to heparin or LMWH. A study published in 2013 was halted prematurely because of poor patient recruitment, but has been cited as evidence of aspirin noninferiority compared with dalteparin treatment.

Anticoagulation

A seminal work by Barritt and Jordan was a small and technically poor study that seemingly demonstrated the efficacy of anticoagulation for the prevention of progression of VTE following initial diagnosis. Although their methods were flawed, several more rigorous subsequent studies have proven the benefit of anticoagulation on morbidity and mortality.

Current options for anticoagulation in VTE include

• 1.
  

  Anticoagulation with heparin or a LMWH, with transition to a VKA until the INR is greater than 2 on 2 consecutive days

  
  
• 2.
  

  Oral dabigatran or edoxaban after 5 days of heparin or LMWH

  
  
• 3.
  

  Oral apixaban or rivaroxaban only, with loading doses

  
  
• 4.
  

  LMWH treatment only for those patients with active cancer

Treatment options regarding anticoagulation are categorized by the mechanism or class of drug when studied or described in the literature.

Unfractionated heparin

Unfractionated heparin (UFH) is an anticoagulant that complexes with antithrombin III (ATIII), producing a conformational change and converting the ATIII molecule into a potent inhibitor of thrombin. ATIII exerts its anticoagulant effect through inhibition of thrombin and factor Xa.

UFH is delivered intravenously and requires partial thromboplastin time (PTT) monitoring. The range of PTT depends on reagent and desired coagulation parameters. A fixed ratio of 1.5 to 2.5 times the control value is suggested but often results in variable and subtherapeutic degrees of anticoagulation. More ideal is the correlation of PTT values with ex vivo values of antifactor Xa between 0.3 and 0.7 u/mL. Weight-based nomograms are often used to estimate the amount of heparin required for anticoagulation. Adverse effects include hemorrhage in up to 7% of patients and osteoporosis in patients with prolonged (longer than one month) use. The risk of hemorrhage is affected by age and concomitant use of thrombolytic or antiplatelet agents. Heparin-induced thrombocytopenia (HIT) is an immune-mediated phenomenon defined by the presence of heparin-dependent immunoglobulin G (IgG) antibodies, which appear to activate platelets in a complex of heparin, platelet, and platelet factor 4, occurring in up to 2.7% of patients receiving heparin. The thrombocytopenia can be complicated by thrombotic events, likely through platelet activation, and usually occurs on or after day 5 of heparin therapy. Patients with a history of HIT should receive heparin alternatives to anticoagulation.

Low Molecular Weight Heparins

LMWHs differ from unfractionated heparins in their pharmacokinetic and biologic properties, namely decreased plasma protein binding and increased serum bioavailability when delivered via a subcutaneous route. LMWH drugs can thus be administered subcutaneously, do not require frequent laboratory monitoring, and exhibit fewer biologic phenomena than unfractionated heparin.

A 1999 meta-analysis found the use of LMWH decreased mortality in the treatment of DVT when compared with UFH. In addition, the LMWH products demonstrated similar safety profiles with respect to bleeding and were as effective as UFH in preventing recurrent DVT. Most patients can be treated safely and effectively with LMWH, with appropriate infrastructure in place. Outpatient treatment with LMWH is reasonable in many patients, provided a high risk of bleeding (very advanced age, recent surgery, history of renal of liver disease), serious coexisting illness, and massive thrombosis are absent. Direct comparisons of LMWH and UFH have shown lower VTE recurrence rates, less major bleeding, and lower mortality rates with treatment using LMWH.

In patients who have recurrent VTE on long-term LMWH (and are believed to be compliant), increasing the dose of LMWH by one-quarter to one-third is recommended. Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt evaluation for underlying malignancy, antiphospholipid syndrome, evaluation of compliance with anticoagulation, and whether the perceived recurrent VTE is an acute finding or a chronic VTE.

In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or NOACs and are believed to be compliant, the CHEST guidelines recommend switching to treatment with LMWH, at least temporarily.

Specific adverse events associated with LMWH include the HIT phenomena, as well as bleeding. LMWH can cross-react with the antibodies that cause HIT and should thus be avoided in patients with a history of HIT. Use of LMHW (dalteparin) in women during pregnancy demonstrated less decline in bone mineral density compared with UFH during and no significant difference in osteoporosis 3 years after delivery, compared with healthy women who did not require anticoagulation.

Warfarin and Vitamin K Antagonists

VKAs include warfarin, acenocoumarol, phenprocoumon, and others, which inhibit gamma carboxylation of factors II, VII, IX, X, C, and S. Drug absorption is rapid and complete, but therapeutic levels take 4 to 5 days to obtain, owing to the mechanism of action of the drugs.

VKA therapy is traditionally started on the same days as parenteral anticoagulation with heparin or LMWH and titrated to an INR of 2 to 3. A small randomized controlled trial demonstrated a significant reduction (20% vs 6.7%) in VTE recurrence in those patients treated with intravenous unfractionated heparin and transitioned to a vitamin K antagonist versus a vitamin K antagonist alone, respectively. Utilized at an INR of 2.0 to 3.0, VKAs have been shown to reduce the risk of recurrent thromboembolism. INRs higher than 3 have demonstrated increased risks of bleeding without benefit of reduced recurrence of DVT. Although INRs higher than 3 were recommended for the management of DVT in patients with antiphospholipid syndrome, 2 trials failed to demonstrate superiority compared with standard (INR 2–3) recommendations.

In trials comparing VKA therapy to novel (or direct) oral anticoagulant therapy, VTE recurrence rates for LMWH/VKA therapy were 2.2% to 3.5% in patients treated for 3 to 12 months, with a risk of major bleeding 8.5% to 10.3%. A large VTE registry found VTE recurrence rates of 2.5%, similar to recent trials, but increased risk of major bleeding, about 2.5% beyond that seen in the same trials.

In addition to bleeding risks, adverse effects of warfarin therapy include vascular purpura and consequent skin necrosis in the first few weeks of therapy, which has been associated with protein C deficiency and malignancy. Coumarin derivatives are known teratogens and should be avoided in pregnancy. The rate of recurrent DVT while on well-coordinated VKA is about 2%. The risk of bleeding at 90 days is about 2.2%. Long-term therapy with VKAs has demonstrated decreased risks of recurrent VTE compared with short-term (3 months) therapy (relative risk 0.20), but was associated with increased risks of bleeding (relative risk 3.44) and no significant difference in mortality.

Novel (Direct) Oral Anticoagulant Therapy

The direct or novel oral anticoagulant therapies differ from VKAs in mechanism, from UFH and LMWH at their sites of action, and from argatroban, in that these novel medications are orally bioavailable. Dabigatran, like argatroban, is a univalent direct thrombin inhibitor, inhibiting thrombin (factor IIa) at its active site. Rivaroxaban, apixaban, and edoxaban are factor Xa inhibitors. Collectively, the NOAC drugs exhibit relatively rapid onsets of action, with peak levels being achieved 1 to 4 hours after oral dosing. The half-lives approximate 12 hours. Advantages of these therapies include ease of dosing, lack of need for monitoring, and improved management for anticoagulation for procedures that might cause bleeding. In support of this is the fact that antifactor IIa and antifactor Xa activities are directly proportional to drug levels. Renal function plays a large role in the elimination of these drugs, and compromised renal function may lead to accumulation, supratherapeutic drug levels, and consequential bleeding. Apixaban and Rivaroxaban have the advantages of not requiring heparin bridging to attain therapeutic levels. In addition, the NOACs have far fewer drug-drug interactions when compared with warfarin, allowing for more stable levels and drug effects. It is important to note that potent inhibitors or inducers of CYP3A4 or p-glycoproteins can affect NOAC drug levels.

All of the trials for the NOACs were designed as noninferiority trials when compared with LMWH or VKAs, although different criteria for noninferiority were utilized across studies. The details of individual trials are discussed, but in general, consistent findings of noninferiority of the NOACs were present throughout. Recurrence rates for VTE in these trials was about 2% for DOACs compared with 2.2% for VKAs; however, study parameters for duration of treatment differed among the trials. Recent meta-analyses showed similar rates of recurrent DVTs between the NOACs and traditional therapies but reduced rates of major and fatal bleeding, as well as all-cause mortality with the NOACs. A significant reduction in bleeding among the NOACs was noted, with a number needed to treat (with NOAC as opposed to VKAs) between 19 and 167. There are limited real-world data to determine the outcomes for patients outside of the selected study groups for the phase III trials for these drugs.

Direct Thrombin Inhibitors

Factor Xa Inhibitors