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WHAT'S NEW IN COAGULATION: JANUARY 2011

Aspirin May Be More Effective At Preventing Cancer Deaths Than Previously Thought.

In the advertisements for aspirin, they for years have called it a wonder drug, and a good many doctors believe it is something of a wonder. Millions of people take a half aspirin every day, for example, for heart health." Now, a newly published paper in The Lancet indicates that "aspirin may be much more effective than anyone knew at helping prevent cancer deaths.The "stunning finding came while researchers were studying 25,000 people taking daily aspirin to prevent heart disease, It turns out aspirin was doing something else, reducing the death rate from cancer as well, in the trials where people have taken aspirin four, five, six, seven years on average, the risk of dying of cancer was reduced by about 25%.

Should everyone take low-dose aspirin? Today the American Cancer Society said no and that 'it would be premature to recommend people start taking aspirin specifically to prevent cancer,'" considering that "even low dose aspirin can lead to dangerous internal bleeding. Still, evidence that it might help fight cancer is intriguing for doctors. Researchers at Oxford reached that conclusion after examining "the cancer death rates of 25,570 patients who had participated in eight different randomized controlled trials of aspirin that ended up to 20 years earlier. Participants who had been assigned to the aspirin arms of the studies were 20 percent less likely after 20 years to have died of solid tumor cancers than those who had been in the comparison group taking dummy pills during the clinical trials, and their risk of gastrointestinal cancer death was 35 percent lower. The risk of lung cancer death was 30 percent lower, the risk of colorectal cancer death was 40 percent lower, and the risk of esophageal cancer death was 60 percent lower.

Only "one-third of people in the analysis were women -- not enough to calculate any estimates for breast cancer, there appeared to be no benefit to taking more than 75 milligrams daily. In addition, "aspirin was not found to [significantly] influence the risk of death from pancreatic, prostate, bladder, kidney, brain, or blood cancers       

Low-Dose Aspirin May Improve FOBTs' Ability To Detect Colon Cancer.

Taking a low-dose aspirin prior to having a fecal occult blood test appears to increase the ability of the test to detect colorectal cancer. It appears that low-dose aspirin use increases the likelihood of bleeding from a colorectal tumor, thus increasing the odds that the test will detect blood. Before reaching that conclusion, researchers evaluated 1,979 patients, 233 of whom "were regular low-dose aspirin users, and 1,746 never used it. Specifically, researchers analyzed the sensitivity and accuracy of two fecal occult blood tests in detecting advanced colorectal neoplasms, tumors that can either be malignant or benign.

Investigators eventually discovered that "the sensitivity of the hemoglobin FOBT for detecting advanced neoplasms among the aspirin users was 70.8% (95% CI 48.9 to 87.4) compared with 35.9% (95% CI 28.9 to 43.4, P=0.001) among nonusers. For another fecal test -- the hemoglobin-haptoglobin test -- the sensitivity among low-dose aspirin users was 58.3% (95% CI 36.6 to 77.9), and 32% (95% CI 25.3 to 39.4, P=0.01) among nonusers.

Experimental Agent May Rapidly Curtail Bleeding In Certain Hemophilia Patients.

According to research presented at a hematology meeting, "an experimental agent that closely mimics normal human clotting appears to rapidly curtail bleeding episodes in patients with hemophilia that is complicated by inhibitors against clotting factors." In fact, "in a phase II study, treatment with the recombinant factor VIIa analog stopped bleeding within nine hours in 41 of 42 patients (97.6%) treated with the three highest doses of the new compound called NN1731." What's more, "the treatment with recombinant Factor VIIa (Novoseven) stopped bleeding in 17 of 19 patients (89.5%). 

EINSTEIN Data Support Rivaroxaban for DVT/VTE Treatment, But Duration Debated

The new oral anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson) is one of a number of new agents that could change the way that patients with deep vein thrombosis (DVT) and venous thromboembolism (VTE) are treated. The findings of two studies were presented, the EINSTEIN acute-DVT study and EINSTEIN-Extension. This new treatment regimen of oral rivaroxaban can potentially make blood-clot therapy easier than the current standard treatment for both the patient and the physician with a single drug and simple fixed-dose approach.

The two studies have been combined into one paper, appearing simultaneously in the New England Journal of Medicine [1], and this, he says, "has worked out well, in the sense of it tells you what to do initially if you are confronted with a patient with DVT and then if you've completed treatment for six to 12 months. It's the combined perspective that is important--how to interpret both studies together being interpreted as really saying we shouldn't stop therapy after six to 12 months in that middle group of idiopathic patients. The study that clinicians want to see is patients randomized to warfarin or a new anticoagulant. "EINSTEIN-Extension won't drive clinical practice that much because the control group was placebo,it does, at least, show that rivaroxaban prevents recurrences if taken and that the bleeding risk of this drug is very low, so it could broaden the indication for extended therapy.

Trials where other new anticoagulants, such as the thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) are being compared with warfarin for extended treatment of venous thromboembolism, are ongoing.

Rivaroxaban Looks Good in EINSTEIN DVT, But Cost an Issue

Rivaroxaban--as a single-drug approach--just makes life easier and is at least as good as standard therapy," he says. This trial and others with competing agents in the same indication mean that the treatment of VTE will increasingly move out of the hospital into the community, he says.

Both Baglin and Silverstein agree that the EINSTEIN acute-DVT data are informative. "There's no doubt that if you stick the two drugs side by side (warfarin and rivaroxaban) that you would use the new drug," says Baglin, "but the problem is cost." In the UK, it currently costs less than £100 a year to keep a patient on warfarin, he says, compared with the current cost of around £1500 a year for the newer anticoagulants. He acknowledges, however, that cost issues will be different in different markets.

Both rivaroxaban and dabigatran are already approved for the prophylaxis of DVT and VTE in patients undergoing knee and hip surgery in the EU and some other markets, but neither has been cleared for marketing in the US. Now that both have phase 3 data on the treatment of DVT, it remains to be seen when they will be filed for approval in this indication.

American College of Chest Physicians (ACCP)--now recommend continuing therapy for this group of "medium-risk" patients indefinitely. However, in practice, this decision is never clear-cut, they say, and must be made on an individual basis. It is this group of "medium-risk" patients who were included in the EINSTEIN-Extension study. The results showed that recurrent VTE events occurred in 7.1% of the 594 patients treated with placebo, so "93% of patients did not have a recurrent event," compared with 1.3% of 602 patients taking rivaroxaban (82% reduction, p<0.001). Bleeding was minimal with the study drug: nonfatal major bleeding occurred in 0.7% of patients on rivaroxaban compared with none in the placebo group (p=0.11). Clinically relevant nonmajor bleeding occurred in 5.4% of rivaroxaban patients and 1.2% of placebo recipients, respectively. EINSTEIN-Extension tells us that rivaroxaban stops thrombosis, but it doesn't tell us that it's better than warfarin at doing this." The threshold that is currently used, he says, is that "if the annual risk [of a recurrent thromboembolic event] is >5%, you should stay on therapy indefinitely, but if it's below that you should stop."

Which Patients With Pulmonary Embolism Can Be Treated at Home?

Patients with pulmonary embolism (PE) are usually treated in the hospital, but suggests that about half of these patients could be treated at home, which would reduce costs, inconvenience, and the risk for infection.

Patients with PE are usually treated in hospital and stay for an average of 10 days; this study suggests that half could be treated at home with similar results, which would reduce costs and improve their quality of life. 

One of the problems is deciding which patients would be suitable for treatment at home, and which are at higher risk and need to be treated in the hospital, he said. To address this issue, his team developed the Hestia criteria, an 11-point questionnaire that evaluates patients for risk. In their study, only patients who met all 11 criteria were allowed to be treated at home; the rest of the patients were treated as inpatients. For their study, screened 581 patients with acute PE and found that 297 patients (51%) met the Hestia criteria and were treated at home. These patients were sent home within 24 hours of being diagnosed with PE and all received weight-adjusted therapeutic doses of low–molecular weight heparin, followed by vitamin K antagonists.

After 3 months, 6 patients had recurrent venous thromboembolism (2%).This was not a randomized trial, so there is no direct comparison between these patients and those who were treated in hospital,  but historical controls show a recurrence rate of 1% to 3% among inpatients, so the 2% seen in the patients treated at home is in the same range, he said. There were 3 deaths in the 3 months after treatment: 2 from cancer and 1 from an intracranial hemorrhage, but the latter occurred in a patient with uncontrolled hypertension,  In addition, 2 patients experienced major bleeding (0.7%). This also compares favorably with historical controls of patients treated in hospital.

The next step will be validation in a randomized trial, Known as Vesta, the trial will take about 1 to 2 years to carry out, so results should be available in about 2.5 years' time, he said.

The Hestia Criteria.

Clinical Prediction Rule for VTE Recurrence Risk in Cancer Patients

Cancer patients are known to be at increased risk for venous thromboembolism (VTE); once they develop a clot, they are treated with long-term anticoagulants to prevent a recurrence. Current guidelines recommend 6 months of therapy with low-molecular-weight heparin (LMWH), and suggest that anticoagulation therapy be continued as long as the cancer is active. But do all cancer patients who have had a VTE need to be treated this way?

The study demonstrated for the first time that cancer patients with VTE vary in their risk for VTE recurrence. Using a new scoring system, identified factors that predicted patients who were at low risk for VTE recurrence (4.5%) and those who were at high risk (19.7%).

In the future, a cancer patient with VTE can be assessed using this scoring system, she said in an interview. Patients who are identified as being at high risk for recurrent VTE can be given more aggressive treatment, and those identified as low risk can be given less intensive anticoagulation therapy, or perhaps none at all. The scoring system was developed on the basis of retrospective data, and it needs validation in a prospective study, which is already planned, she said.

This study is a good first step toward a clinically feasible scoring system to stratify cancer patients who have already had a clot according to their risk of having a VTE recurrence.

New Scoring System

The charts of 543 cancer patients with VTE were reviewed followed from 2002 to 2004 and in 2007 and 2008 at the Thrombosis Unit at The Ottawa Hospital.

During the first period (2002 to 2004), most of the patients were taking oral vitamin K antagonists, usually warfarin; during the second study period (2007 and 2008), most were receiving subcutaneous LMWH. This reflects a change in practice, which was incorporated into treatment guidelines after the publication of the CLOT study in the New England Journal of Medicine (2003;349:146-153), she explained. The CLOT study showed that LMWH halves the risk for a VTE recurrence, compared with oral vitamin K antagonists (9% vs 17%, a 52% reduction).

Overall, 10.1% of patients developed a second clot during the first 6 months of anticoagulant therapy. The rate was 10.5% among patients receiving LMWH (36 of 343 patients) and 9.5% among those receiving oral vitamin K antagonists (19 of 200 patients). A multivariate analysis of the data identified independent risk factors. Being female, having the primary tumor site in the lung, and having a history of VTE all increased the risk for VTE recurrence. In the new scoring system, each of these was allocated 1 point. Breast cancer and stage 1 disease appeared to have a lower risk, and these were each allocated –1 point.

However, during the discussion that followed the presentation, a delegate questioned the fact that being female increased the risk for VTE recurrence among cancer patients with VTE, because in the general population, it is males that are at higher risk. Dr. Louzada said she had no explanation for this observation. Another delegate asked about hematologic malignancies. Dr. Louzada said these appear to lower the risk, but the number of patients was so small, they decided not to include this as an independent risk factor.

The researchers calculated the points for each patient, and then calculated the frequency of VTE recurrence in each patient group.

VTE Recurrence Rate According to the Sum of Points in the Model

Patients scoring –3 to 0 are at low risk for VTE recurrence, and patients scoring from 1 to 3 are at high risk. In this patient cohort, 48% were calculated to be at low risk (a rate for VTE recurrence below 5%).

The model also identifies patients who are at very high risk for VTE recurrence, and it could be feasible to intensify anticoagulation therapy in this population, he noted.

Stroke Cause Predicts Outcome After Thrombolysis

Patients with acute ischemic stroke due to small-vessel disease (SVD) have few bleeding complications after intravenous thrombolytic therapy and the best outcomes of all stroke causes, even after adjusting for confounding factors, such as baseline stroke severity. Several studies have shown SVD to be associated with good outcomes, the study team notes.

To investigate the independent impact of stroke cause on outcome, they analyzed 957 patients with acute ischemic stroke who were treated between 1995 and 2008 with appropriate and timely intravenous thrombolytic therapy at a comprehensive stroke center in Helsinki. They used multivariate logistic regression to compare clinical outcome of the stroke subtypes by 3-month modified Rankin Scale (mRS) score; a good outcome was defined as mRS score of 2 or less.

Of the 957 study subjects, 389 (41%) had cardioembolism, 217 (23%) had large-artery atherosclerosis, and 101 (11%) had SVD. The remaining 250 patients had stroke classified as other determined cause (n = 27, 2.8%), multiple causes (n = 28, 2.9%), undetermined cause with extensive workup (n = 130, 14%), and undetermined cause but incomplete evaluation (n = 65, 6.8%). There were no significant differences in onset-to-needle times among the etiologic subgroups.

Compared with patients without SVD, those with SVD were more often male (64% vs 11%; P < .05) and more apt to have had a prior stroke (20% vs 11%; P < .05), the researchers report. Patients with SVD also had significantly lower National Institutes of Health (NIH) Stroke Scale scores at baseline and after thrombolytic therapy at 2 hours, 24 hours, and 7 days. Hypertension, diabetes, hypercholesterolemia, and transient ischemic attacks were found equally in all subtypes.

According to the researchers, patients with stroke due to SVD were more likely to have a good outcome than their peers with stroke due to other causes, even after adjustment for baseline NIH Stroke Scale score, glucose level, age, and hyperdense artery sign (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.01 – 3.23). The median mRS score at 3 months was significantly lower (P < .01) in the SVD group, and more of these patients had a good or excellent outcome (P < .001 for both), they note.

The rate of intracranial hemorrhage was significantly lower in the SVD group than in the other groups (2.2% vs 22%; OR, 0.07; 95% CI, 0.02 – 0.29; P < .001). No patient with SVD had symptomatic intracranial hemorrhage. These intracranial hemorrhage rates in SVD stroke, they say, are in line with other studies.

Mortality was also significantly lower in the SVD group relative to the other groups (1.0% vs 11.6%; OR, = 0.8; 95% CI, 0.01 – 0.57; P = .001).

Stroke. Published online November 24, 2010.

ADVANCE Analysis: Apixaban Effective, Safe, for VTE Prevention Following Hip/Knee Surgery

Pooled data from the ADVANCE clinical-trial program shows that apixaban (Bristol-Myers Squibb/Pfizer), a novel factor Xa inhibitor, is more effective than enoxaparin (Lovenox, Sanofi-Aventis) for the prevention of major venous thromboembolism (VTE) in patients undergoing hip- or knee-replacement surgery.

The findings show that major venous thromboembolism, clots in the large veins in the thigh or those that have already moved to the lungs and caused symptoms, was reduced by a little over half, from 1.5% in the enoxaparin group to 0.7% in the apixaban group. The absolute reduction of 0.76%, or about eight patients per 1000 treated, means that for every 125 patients treated with apixaban, by comparison with enoxaparin, we would prevent one episode of major venous thromboembolism.

Overall, rates of major bleeding were low and similar in both treatment arms, with major bleeding occurring in 0.74% of patients in the apixaban group and 0.77% in the enoxaparin-treated group. In addition, major bleeding at the surgical site occurred in 26 of the apixaban patients and in 27 of the enoxaparin patients.The lack of an increased risk of bleeding with apixaban is particularly reassuring, given that Bristol-Myers Squibb and Pfizer stopped the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome (ACS) because of increased bleeding that would not be offset by reductions in ischemic events. As reported by heartwire , the data and safety monitoring board (DSMB) recommended that the trial be halted a few weeks ago.

Researchers Explore Rates Of Clopidogrel Discontinuation, Reasons For Stopping.

In a paper published online December 22, 2010 in the American Journal of Cardiology, explored rates of clopidogrel discontinuation -- and reasons for stopping.  66 out of 400 patients discontinued use of the drug within a month. The researchers found that "the number-one reason given was the cost of the drug (two-thirds of those who stopped), followed by a sense that they were not provided with adequate information at discharge as to why they should stay on the medication (almost one in five patients who stopped). In 15% of cases, those who stopped did so on the recommendation of another physician.

New Study Finds Warfarin Could Be Better Utilized For Stroke Prevention.

A new study found the blood thinner warfarin is only used by about half of elderly patients with abnormal heart rhythms who could use the drug to prevent strokes. The study also found warfarin users had more doctor visits but fewer hospitalizations.

Ticagrelor Associated With Lower Mortality From CABG Compared With Standard Clopidogrel.

The novel reversible antiplatelet agent ticagrelor (Brilinta) was associated with lower mortality from coronary artery bypass graft surgery (CABG) compared with standard clopidogrel (Plavix), according to a subanalysis of the pivotal PLATO trial. Investigators found that, "compared with clopidogrel, ticagrelor cut total mortality by a relative 51% (4.7% versus 9.7%, P<0.01) and cardiovascular mortality by 48% (4.1% versus 7.9%, P<0.01)." The researchers found that "the mortality advantage came with no excess bleeding risk." The research is published online in the Journal of the American College of Cardiology. HeartWire (12/29, Nainggolan) also covered the story.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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