Blood clots: An updated guide from the experts
Two primary-care organizations have issued new recommendations that will enhance your ability to diagnose and treat venous thromboembolism.
Early treatment of deep venous thrombosis (DVT) is crucial to avoid pulmonary embolism (PE) and other complications, but staying abreast of all the new developments in diagnosing and managing the condition is a big challenge. Now two primary-care medical organizations have stepped forward with updated guidelines that have made the task easier.
There are actually two sets of recommendations, one on diagnosis, prepared by the American Academy of Family Physicians, and one on treatment, written by the American College of Physicians. Both sets of guidelines were issued simultaneously earlier this year and published in the organizations’ respective journals (Table 1).
“There have been a lot of profound changes in the approach to this condition over the past few years, and the consequences of inappropriate treatment are significant,” says one of the authors, Lee Green, MD, professor of family medicine at the University of Michigan in Ann Arbor. Those consequences can be grave and include increased morbidity and mortality.
What follows is a brief summary of the most important recommendations from the two expert panels.
The early diagnosis of venous thromboembolism (VTE) can be complex and elusive because tests involve a tradeoff between sensitivity and specificity (Table 2). “The single most important concept behind the guidelines is that a diagnostic strategy must take into account probability,” Dr. Green says. “No one test can rule in or rule out VTE under all circumstances.”
Clinical features are only predictive when combined in a formal protocol, the guidelines point out. Among the several schemas available, the authors endorse the “Wells Prediction Rule,” introduced in 2003, because of its comparatively strong evidence base. According to Wells, one point is assigned for each of the following:
• “Active” cancer (treatment within six months)
• Paralysis, paresis, or recent plaster immobilization of the legs or feet
• Recently bedridden longer than three days or major surgery within 12 weeks and requiring anesthesia
• Localized tenderness along the deep venous system
• Swelling of the entire leg
• Calf swelling 3 cm larger than asymptomatic side
• Pitting edema confined to the symptomatic leg
• Collateral superficial veins
From the sum you reach, subtract two points if there is an alternative diagnosis at least as likely as DVT. If the final score is 0, the probability of VTE is low; if the score is 1-2, the probability is intermediate; and if the score is ≥3, the probability is high. There is a similar scorecard for diagnosing PE.
Wells scores are more meaningful in younger patients who have no history of VTE or significant comorbidities. “You have to have a higher level of suspicion when treating older patients, and particularly for patients who are very sedentary or disabled, or who suffer from a chronic illness like heart failure or malignancy,” Dr. Green advises.
The role of D-dimer testing
The primary role of the Wells score is to direct further evaluation and provide a context for findings. When the score indicates a low probability of VTE, a high-sensitivity D-dimer assay is “a reasonable option.” (For those at intermediate-to-high risk, according to Wells, the assay adds no useful information.)
D-dimer testing is not in itself diagnostic but can sharpen the predictive power of the Wells approach, resulting in a more meaningful probability estimate. Applied appropriately, the combination has high negative predictive value; a review of 11 studies found that for patients with a low Wells score and negative D-dimer, the incidence of VTE over the next three months was a mere 0.5%. In young patients with symptoms of short duration and without complicating factors or comorbidities, combined Wells and D-dimer findings may be enough to make imaging studies unnecessary.
The positive predictive value of D-dimer assay is poor, however, particularly in elderly and debilitated patients. “Many things other than VTE can elevate D-dimer—heart failure, and pulmonary disease, for example,” Dr. Green cautions. Two meta-analyses evaluated sensitivity and specificity of two D-dimer assay methods—enzyme-linked immunosorbent assay (ELISA) and latex turbidimetric assay. Results were similar: Sensitivity was 93%-95%, and specificity 45%-51%.
When to perform ultrasound or venography
The guidelines recommend ultrasound for patients judged to be at intermediate-to-high risk of DVT. While this test has high sensitivity and specificity for proximal vein thrombosis, systematic reviews find considerably less predictive value for thromboses in veins below the knee, particularly in asymptomatic patients.
Consequently, a negative ultrasound can effectively rule out proximal vein thrombosis, but not calf thrombosis. For patients in whom the latter is suspected, repeat ultrasound or venography may be indicated. “Contrast venography is still considered the definitive test to rule out the diagnosis of DVT,” the guideline says. (Dr. Green makes it a point to clarify, however, that false positives and negatives have been known to occur with venography, although at a lower rate than with other tests.)
The consequences of a missed diagnosis of distal DVT are less serious than for proximal DVT, although they are not negligible; while PE is unlikely, post-thrombotic syndrome remains a definite risk.
Managing VTE: Big changes
Management of VTE is “very different from what it was just a few years ago,” Dr. Green says. The biggest change has been the advent of low-molecular-weight heparin (LMWH) as a first-line option. The guidelines propose that LMWH, rather than unfractionated heparin, should be used whenever possible for acute treatment of DVT. Because the evidence is less convincing regarding PE, either LMWH or unfractionated heparin is appropriate for this condition.
A review of 13 trials found consistent, convincing evidence for the superiority of LMWH over unfractionated heparin in reducing mortality and major bleeding. In nine of 10 reviews, there were fewer deaths over the subsequent three- to six-month period with LMWH. There was also evidence, albeit less consistent, that the drug more powerfully reduces recurrent DVT. The treatment guidelines point out, however, that more recent reviews find the magnitude of the LMWH advantage to be somewhat smaller than had earlier been reported.
From a practical point of view, in Dr. Green’s opinion, there is no choice. “Unfractionated heparin adjusted by lab values is terribly difficult to manage and is labor-intensive. The patient spends a great deal of time under or over the therapeutic range.” If LMWH has a small advantage in the carefully controlled, well-staffed setting of a clinical trial, he says, “the advantage in the real world is much greater.”
The other area in which the evidence reviewed for the guidelines supports significant change from earlier practice is its validation of outpatient treatment. For DVT and possibly for PE, the outpatient use of LMWH appears to be safe and cost-effective and should be considered for appropriate patients in sufficiently supportive circumstances.
A number of studies have compared the outcome of initial VTE treatment delivered in inpatient and outpatient settings. In 12 of them, the outpatient regimen was with LMWH while inpatients received unfractionated heparin; in five, LMWH was used in both settings. Brief hospitalization for stabilization was permitted before randomization in at least eight of the studies. Prior history of VTE, thrombophilic conditions, comorbid illness, and probable difficulties with adherence were grounds for exclusion from most studies. Patient education and adequate home-care support were invariable features of the outpatient condition.
In no study did setting make any significant clinical difference; recurrent DVT was rare (0%-9%), as was major bleeding (0%-4%). Few cases of PE were seen. Mortality during follow-up (with oral anticoagulation) ranged from 0%-18%. Of the 10 studies that reported on treatment costs, nine suggested savings with the outpatient regimen.
The guidelines endorse the routine use of compression stockings, starting within a month after diagnosis of DVT and continuing for at least a year, to reduce the risk of post-thrombotic syndrome.
This is “a seriously underutilized treatment,” according to Dr. Green. (Though no standardized definition of post-thrombotic syndrome has been established, it is usually taken to mean chronic postural dependent pain and edema or localized discomfort, in the context of a history of DVT.)
The guidelines base their recommendation on just three randomized controlled trials. Two studies compared outcomes among patients who did not use stockings to those who wore custom-made or sized-to-fit stockings soon (one week or one month) after the DVT episode. Rates of post-thrombotic syndrome in the stocking groups were roughly half those in the control groups. In one of the studies, the rate of severe syndrome was reduced even more dramatically (3% vs. 11%) with stockings.
Use of the stockings, apparently, must begin early; a study that randomized patients to compression stockings or nonsupportive hose a year after the initial event found no difference in outcome.
Pregnancy and VTE
Pregnancy greatly increases VTE risk—episodes are five times as common in mothers-to-be as in nonpregnant women. But, as the guidelines note, there isn’t sufficient evidence to make specific recommendations for anticoagulation management.
Although VTE prophylaxis during pregnancy has been studied extensively, only 11 studies involving treatment were available for review, and these were observational and for the most part underpowered as to outcome. Fewer than 200 women in these studies were treated with LMWH.
Clinicians are cautioned to avoid vitamin K antagonists for anticoagulation, because they cross the placenta and are associated with embryopathy (at between six and 12 weeks’ gestation) as well as fetal bleeding, including intracranial bleeding, at delivery. Heparin in its various forms does not cross the placenta and is not associated with embryopathy or fetal bleeding.
Length of treatment
Anticoagulation with a vitamin K antagonist should be maintained for three to six months when the VTE episode is related to a transient risk factor (such as a leg immobilized in a cast after a fracture or a stay in a burn unit), and for more than 12 months when VTE is recurrent or idiopathic.
An analysis of 10 trials that used radiologic documentation found enormous variation in the rate of recurrence, depending on the etiology of the index episode and a history of prior thrombotic events. The one study that included only second-episode patients found significantly fewer recurrences of VTE among patients receiving long-term therapy than those whose treatment was terminated after six months. When the cause was identifiable and transient, recurrences were no more common after a three-month course of treatment than after a six-month course.
The guidelines endorse the use of LMWH for long-term treatment in place of oral anticoagulation for certain patients. The authors reviewed 10 randomized controlled trials that compared the two drug classes and found the risk of VTE recurrence or of bleeding to be no higher with LMWH than with vitamin K antagonists. The largest of these trials found significantly fewer recurrences (4% vs. 11% for DVT and 4% vs. 5% for PE) in the group that received LMWH.
The authors suggest that LMWH may be particularly useful when international normalized ratio (INR) control is difficult and that it may offer superior efficacy for patients with cancer. It also offers an alternative for patients who can’t tolerate vitamin K antagonists or in whom they are contraindicated.