Published in the February 2006 issue of Today’s Hospitalist
With fatal pulmonary embolism topping the list of preventable causes of death in U.S. hospitals, the push is on to standardize DVT prevention, treatment and assessment. There still exists, however, much debate about best practices.
How long, for instance, should physicians prescribe prophylaxis for high-risk patients? What therapies should hospitalists use, particularly for secondary prevention in cancer patients? And what diagnostic tests should physicians order to rule out venous thromboembolic disease?
At a meeting on managing inpatients held last September by the University of California, San Francisco (UCSF), Tracy Minichiello, MD, a hospitalist and assistant professor of medicine at UCSF, outlined several DVT-related controversies roiling hospital medicine.
Dr. Minichiello, who is director of UCSF’s anticoagulation clinic, reviewed new evidence that is helping settle some of the debates. She also provided recommendations on several anticoagulation issues.
Making the diagnosis: the value of CT scans
The challenge with determining the ideal diagnostic strategy for pulmonary embolism is that there is no reliable, reproducible test. While pulmonary angiography was once considered the gold standard for diagnosing PE, it is beginning to fade from popularity.
Dr. Minichiello said that pulmonary angiography now suffers from many of the same shortcomings that plague other diagnostic strategies: interobserver variability and lack of availability. As a result, many hospitalists and emergency room physicians use CT angiography as their initial radiographic test, but many still wonder just how valid the technology is.
“Unfortunately, CT scanning has limited sensitivity for picking up peripheral pulmonary emboli,” Dr. Minichiello pointed out. As a result, she said, even when patients have a negative CT, hospitalists often feel compelled to order more tests to assure themselves that anticoagulation isn’t needed.
New research, however, is helping resolve that ordering dilemma. A meta-analysis published in the April 27, 2005, Journal of the American Medical Association reviewed the results of 15 studies examining more than 3,500 patients with clinically suspected pulmonary embolism who had a negative CT and did not receive anticoagulation.
Most of the subjects had a low pretest probability, had a negative CT and did not receive anticoagulation. Follow-up data examining recurrence were available for at least three months.
Investigators recorded a total of 42 events, a number that Dr. Minichiello described as “incredibly low.”
While Dr. Minichiello urged hospitalists to exercise caution when extrapolating the results of this trial, she said that forgoing additional testing and withholding anticoagulation appears to be reasonable in patients whose pre-test probability of PE is between 10 percent and 20 percent.
Dr. Minichiello added that patients with a higher pre-test probability will still have a fairly high likelihood of disease, even if a CT is negative. As a result, she said that further testing, such as Doppler ultrasound of the lower extremities, will be indicated in these patients.
Prognostication in PE
Dr. Minichiello reviewed preliminary data on the use of CT scanning for prognostication in pulmonary embolism. Patients who present with hemodynamic instability and pulmonary embolism, she noted, have “exceedingly high” rates of in-hospital mortality.
(She also noted that while these high-risk patients are easily identified because their hemodynamic parameters are compromised, you need to keep an eye on another subgroup of patients: individuals with submassive PE, which is defined as evidence of right ventricular dysfunction without hemodynamic compromise. While these patients are hemodynamically stable, Dr. Minichiello said, they still have a higher mortality rate. Be aware that the “eyeball” test will not identify these high risk patients, she noted, and that additional testing is needed.)
While transthoracic echocardiography has become the standard for identifying right ventricular dysfunction in patients with pulmonary embolism, this modality is not always available. It is also expensive, Dr. Minichiello added, and the view of the right ventricle can be suboptimal.
Recently, researchers have looked at the role that CT imaging, a study already available in many patients diagnosed with PE, can play in identifying high risk patients.
“Preliminary studies reveal the ratio of right ventricular dimension to left ventricular dimension measured on CT scan correlates with echocardiography with regard to right ventricular dysfunction,” Dr. Minichiello said. She cited a recent study of more than 400 patients who had a CT-documented pulmonary embolism, underwent echocardiography and were assessed in 30 days for mortality or adverse outcomes.
While the positive predictive value of this strategy is not high enough for physicians to change triage or therapy to more aggressive interventions, “the negative predictive value of CT scanning for adverse outcome in these early studies is very high,” Dr. Minichiello said. “If these findings are validated, we may be able to reduce the need for additional imaging to identify high risk patients.”
Isolated calf vein DVT
While the conventional wisdom holds that calf vein thomboses do not need anticoagulation and can be followed with serial ultrasound, Dr. Minichiello said that view is outdated. Thomboses in calf veins have a higher risk of propoagation than previously appreciated, she told the group, perhaps as high as 20 percent. “They need to be anticoagulated,” she explained.
The risk of recurrence is lower in patients with isolated calf vein thrombosis, so the good news is that therapy may not need to continue as long as in other patients. But Dr. Minichiello said that these patients should receive full-intensity anticoagulation for at least three months, and longer if the event is unprovoked.
Prophylaxis: the longer, the better
When it comes to another debate “how long to give prophylaxis to high-risk patients “recent research has weighed in with a simple message: Longer is better, at least in the highest risk groups.
In one study looking at patients undergoing hip fracture repair, all participants received usual prophylactic care, or seven to 10 days of fondaparinux. Half of the subjects, however, also received extended prophylaxis, with the therapy continuing for three weeks.
“Almost 40 percent of the patients in the usual-care arm developed DVT,” Dr. Minichiello said, “compared to less than 2 percent of patients who received extended prophylaxis.” The number needed to treat was about three.
When considering symptomatic events only, the number needed to treat jumps to 41, but she noted that number is still below the widely accepted threshold of 50.
Based on these and other data, the American College of Chest Physicians issued new recommendations in 2004 regarding DVT prevention in hip fracture and hip arthroplasty patients. The group said that all patients should receive 10 days of prophylactic anticoagulation, and it urged clinicians to consider extended prophylaxis (28 to 35 days), especially in patients with additional risk factors. That latter group includes individuals with COPD and congestive heart failure, as well as patients who are elderly, have delayed mobility and have a history of DVT or cancer.
Cancer patients undergoing surgery constitute another high-risk group. These patients face twice the risk of postoperative DVT as non-cancer patients, Dr. Minichiello pointed out, and their risk of fatal pulmonary embolism is three times that of patients who are cancer-free.
Two studies compared a typical course of prophylaxis ” seven to 10 days of low-molecular-weight heparin “to extended prophylaxis for three weeks. (One study used enoxaparin, while the other tested dalteparin.) Both studies found significant risk reduction with extended prophylaxis “and no significant difference in either major or minor bleeding.
At the 2004 annual meeting of the American Society of Hematology, experts recommended extending prophylaxis post-discharge. Dr. Minichiello said preventing DVT in this population is important not only because cancer patients have a high risk of post-operative thrombosis, but because “the risk of recurrent thrombosis and anticoagulation-related bleeding is much higher in cancer patients with venous thromboembolic disease. Prevention is clearly the way to go in this population.”
Treating cancer patients
Patients who have both active cancer and DVT are the subject of another controversy: What to use for secondary prevention. Standard therapy to prevent recurrent thrombosis in these patients ” low-molecular-weight heparin bridging to full dose warfarin, with an INR goal of two to three “is changing.
“Cancer itself, most notably adenocarcinoma, makes patients hypercoagulable,” Dr. Minichiello said. Both chemotherapy and radiation increase patients’ risk of thrombosis, as does any in-dwelling line.
As Dr. Minichiello has learned first-hand in her own anticoagulation clinic, “it is extremely difficult to manage Coumadin in patients with cancer because their diet is very variable.” These patients typically suffer nausea, vomiting, and diarrhea, and they can have antibiotic induced vitamin K deficiencies.
The CLOT study, which was published in the July 10, 2003, New England Journal of Medicine, identified one promising alternative. Subjects in the study, all of whom had active cancers, initially received standard full-dose therapy with low-molecular-weight heparin.
Half were randomized to transition to warfarin therapy with an INR goal of two to three, while the other half continued low-molecular-weight heparin. The dose was reduced to 75 percent of full dose after one month.
There were 336 patients in each arm of this trial. Fifty three patients in the warfarin group developed recurrence while on therapy, compared to only 27 in the low-molecular- weight heparin group.
Investigators found that low-molecular-weight heparin was associated with a substantial reduction in risk, Dr. Minichiello pointed out, adding that 20 of the 53 recurrent events occurred when patients’ INR was within therapeutic range. In other words, she said, those events can’t be chalked up to poor anticoagulation management.
As a result of those data, the American College of Chest Physicians now recommends that cancer patients with DVT be treated with low-molecular-weight heparin, both in the hospital and in outpatient settings. “They should stay on this therapy for three to six months,” Dr. Minichiello said, “and not be converted to warfarin.”
Edward Doyle is Editor of Today’s Hospitalist.
Smaller is better: a look at the pros and cons of a new DVT therapy
A new DVT therapy that is getting a lot of attention is a good example of how smaller can be better.
The drug, fondaparinux, is the first in a new class of synthetic pentasaccharides. Tracy Minichiello, MD, a hospitalist at UCSF, said that the drug’s molecules are smaller than heparin, which gives it a distinct edge when it comes to anticoagulation.
“It is likely that the small size of fondaparinux interferes with its ability to activate platelets coated with heparin induced antibodies,” Dr. Minichiello said. And while fondaparinux can cause heparin PF4 antibodies, the culprit in heparin-induced thrombocytopenia, she noted that true HIT is unlikely to develop because these platelets cannot be activated.
At UCSF’s annual meeting on managing hospitalized patients, Dr. Minichiello, who is director of UCSF’s anticoagulation clinic, talked about some of the drug’s pros and cons.
On the plus side, fondaparinux has an extremely predictable dose effect and once-a-day dosing. It does not require INR or PTT monitoring, she said, which makes it easier to transition to outpatient therapy.
A meta-analysis of more than 5,000 patients undergoing high-risk orthopedic surgery found that the rate of thrombosis in people taking fondaparinux was 6 percent. In patients taking low-molecular-weight heparin, that number was 14 percent. There was no difference in the number of bleeds.
Dr. Minichiello pointed out that the drug’s convenience and efficacy, however, come with some significant downsides.
Fondaparinux is contraindicated in patients whose creatinine is less than 30. In addition, it doesn’t perform well in patients who weigh less than 50 kg. “There is a very high recurrence rate” in these individuals, she said.
Even more importantly, she pointed out, there is no permanent reversal agent.
“This drug has a 17-hour half life, so it can stick around for between two and four days,” she said. For fully anticoagulated patients, Dr. Minichiello added, “That makes me very nervous because that’s a lot of factor VII or FFP if someone does develop a bleed.”
The bottom line? Choose your candidates for fondaparinux very carefully. “Perhaps outpatients,” she concluded, “who have a lower risk profile may be better candidates.”
Some long-awaited answers about heparin’s anti-tumor effects
While researchers have long suspected that heparin may have anti-tumor effects, only recently have they begun to unlock the secrets of the drug’s anti-tumor mechanisms.
Tumor cells are often coated with fibrin and platelets, which prevent cancer from being attacked by natural killer cells, according to Tracy Minichiello, MD, a hospitalist and director of UCSF’s anticoagulation clinic. Because heparin inhibits the formation of these coatings, the drug helps the body’s natural defenses fight tumor cells more effectively.
Heparin also inhibits the invasive heparinase that targets healthy cells’ endothelium, and it interferes with the receptor that allows tumor cells to attach to the endothelium.
Recently, an analysis of data from the CLOT study provided intriguing evidence of heparin’s anti-tumor activity. While the original study compared the effects of bridging to either low-molecular-weight heparin or warfarin for secondary DVT prevention in cancer patients, the post-hoc analysis also looked at patients’ survival advantages.
Although survival curves for patients receiving low-molecular-weight heparin and warfarin were the same when considering the entire cohort, Dr. Minichiello explained, a subgroup analysis of patients with better prognoses at the start of therapy revealed the therapy produced a benefit. When researchers considered only patients without evidence of metastases at the start of the trial, they found that those treated with heparin had a significant survival advantage when compared to patients who received placebo.
“The probability of death at one year in patients treated with warfarin for a cancer-related clot was 36 percent, compared to 20 percent if they were treated with low-molecular-weight heparin,” Dr. Minichiello said. She added that researchers determined that these findings were not due to fewer pulmonary emboli or clot-related complications.
Those results were duplicated in a study of cancer patients who had no history of DVT or pulmonary embolism, with patients being randomized to either heparin or placebo for one year. (Patients were followed for three years.) “There was a marked survival advantage in patients who were treated with heparin,” Dr. Minichiello said. “Again, this advantage was limited to patients who had earlier stage disease.”
Those findings have already fueled further research, according to Dr. Minichiello. Ongoing trials are now adding heparin to chemotherapy for patients with non-small-cell lung cancer.