Drug dramatically reduces risk of dangerous blood clots in cancer patients

Blood clots in the legs can cause swelling, redness and pain. If a clot forms in the lungs, it can be deadly. New research provides the first approach for safely preventing these clots in people with cancer. Credit: The Ottawa Hospital

A Canadian clinical trial published in the New England Journal of Medicine provides the first approach for safely preventing blood clots (or venous thromboembolism) in people with cancer. About half of people newly diagnosed with a solid cancer could be candidates for the strategy, which involves a low dose of a direct oral anticoagulant called apixaban.

08 dec 2018--"Cancer increases the risk of blood clots, which in turn can cause pain, reduce quality of life and increase the risk of death," said senior author Dr. Philip Wells, a hematologist, senior scientist and Chief of Medicine at The Ottawa Hospital and the University of Ottawa. "Our study shows for the first time that we can safely prevent these clots in many people with cancer."
A key part of the study was the identification of cancer patients with a higher risk of developing blood clots. This was done using the Khorana score, which is based on blood tests results and other clinical factors. The researchers found that about half of all people starting cancer chemotherapy were in the higher risk group. They enrolled 563 of these patients from 13 Canadian centres in the trial and randomly assigned them to receive apixaban (2.5 mg twice a day for six months) or a placebo.
Of the 275 patients in the placebo group, 28 suffered a blood clot within six months (10.2 percent) compared to 12 of 288 in the apixaban group (4.2 percent). The researchers also looked at side effects related to bleeding, as these are known to increase with the use of anticoagulants. Three patients in the placebo group suffered a major bleed (1 percent) compared to six patients in the apixaban group (2.1 percent), but all bleeds were treatable.
"Anticoagulants are commonly used to prevent blood clots in other high-risk groups, but the traditional thinking has been that these drugs would cause too much bleeding in people with cancer," said first author Dr. Marc Carrier, a hematologist, senior scientist and associate professor at The Ottawa Hospital and the University of Ottawa. "Our study shows that if you select the right patients and use a relatively low dose of a direct oral anticoagulant, the benefits easily outweigh the risks."
With about 1.9 million people diagnosed with cancer every year in Canada and the U.S., the researchers estimate that about half, or 950,000 could be considered for the blood clot prevention strategy tested in the study. In this population, the strategy would be expected to prevent clots in six percent, or 57,000 people. The preventative strategy would also save money, as treating blood clots can be very expensive.
This research means a lot to Harold Black, 76, who developed a cancer-associated blood clot in his lungs (pulmonary embolism) in September 2018. The large clot required two days of treatment and monitoring at The Ottawa Hospital, followed by ongoing daily heparin injections in the belly.
"I feel very lucky because I was told that the first sign of a pulmonary embolism is often death," said Black. "If this research prevents people like me from developing blood clots, that will make a big difference for a lot of people."
The blood clot (thrombosis) program at The Ottawa Hospital and the University of Ottawa is the largest and the most research-intensive in the world. With four publications in the New England Journal of Medicine since 2015, their research is transforming lives both in Ottawa and around the world.
"I want to thank the outstanding physicians, nurses, research coordinators and other members of our thrombosis team," said Dr. Wells. "But above all, I want to thank our patients for participating in our research and helping us improve care for them and others around the world."
This study was sponsored by the Ottawa Hospital Research Institute, with funding primarily from the Canadian Institutes of Health Research. The BMS-Pfizer Alliance also provided funding but had no role in designing the study or analyzing the results. The study was also supported by the CanVECTOR research network and the Ottawa Methods Centre. Research at The Ottawa Hospital is possible because of generous donations to The Ottawa Hospital Foundation.

More information: Marc Carrier et al, Apixaban to Prevent Venous Thromboembolism in Patients with Cancer, New England Journal of Medicine (2018). DOI: 10.1056/NEJMoa1814468


Provided by The Ottawa Hospital

Chronic Kidney Disease Predicts Risk for Thromboembolism in Patients with Afib

Chronic kidney disease is an independent predictor of incident thromboembolism among patients with atrial fibrillation, according to a Circulation study published online.

06 mar 2009--Researchers examined data from a U.S. healthcare system on some 11,000 adults with nonvalvular afib and no previous kidney transplant. During roughly 33,000 person-years of follow-up, nearly 700 thromboembolic events occurred while patients were off anticoagulation.

In adjusted analyses, thromboembolism was significantly more common both among patients with reduced estimated glomerular filtration rates than among those with the highest eGFRs (hazard ratio, 1.4), and among those with proteinuria than among those with normal urine tests (HR, 1.5).

The authors say their study suggests that eGFR and proteinuria should be assessed in patients with afib in order to help "improve risk stratification and decision making about the use of antithrombotic therapy to prevent stroke."

LINK(S):

Circulation article (Free abstract; full text requires subscription)

New Guidelines on Venous Thromboembolism in Cancer Patients

The American Society of Clinical Oncology has released new guidelines for prevention and treatment of venous thromboembolism in cancer patients. The guidelines come in the face of a 35% increase in cancer-associated VTE from 1995 to 2002.
Published early online in the Journal of Clinical Oncology, the guidelines recommend the following:
All hospitalized cancer patients should be considered for prophylaxis against VTE, in the absence of bleeding or other contraindications.
Prophylaxis is not recommended for ambulatory patients unless they are under treatment for multiple myeloma with thalidomide or lenalidomide.
Patients undergoing major surgery should be considered for prophylaxis, as well as those undergoing minor surgical procedures lasting longer than 30 minutes. (Prophylaxis should continue for roughly a week, and in high-risk patients after major surgery, it should continue for up to 4 weeks.)
Low-molecular-weight heparin is the preferred agent for treating VTE.

Venous Thromboembolism Rates Climb After Hospital Discharge

HAMILTON, Ontario, July 23 -- Patients are more likely to develop venous thromboembolism after hospital discharge than during their stay, and most get no prophylactic treatment.
Although as many as 10% of hospital deaths can be attributed to pulmonary embolism, most cases of venous thromboembolism are diagnosed in the three months after hospital discharge, Frederick A. Spencer, M.D., of McMaster University here, and colleagues, reported in the July 23 issue of the Archives of Internal Medicine.
The findings emerged from a study of 1,897 patients with an episode of venous thromboembolism confirmed from medical records of in the Worcester, Mass., metropolitan area during 1999, 2001, and 2003.
In all, 73.7% (1,399 patients) developed venous thromboembolism as outpatients. By comparison, only 26% (498 patients) developed the clots while hospitalized.
A substantial proportion of these outpatients had undergone surgery (23.1%) or hospitalization (36.8%) in the preceding three months. The median and mean lengths of those stays were 4.0 and 7.4 days.
Among those patients, 67% experienced deep vein thrombosis within a month of hospitalization.
Of patients who had recently been hospitalized but had not had surgery, 6.9% were diagnosed within one month after discharge, 19.9% between one and two months, and 13.2% between two and three months of discharge.
Among surgical patients, 66.4% were diagnosed with a clot within one month, 18.3% between one and two months, and 15.2% between two and three months after discharge.
Other major risk factors for venous thromboembolism in the outpatient setting included active malignant neoplasm (29.0%) or previous venous blood clot (19.9%).
Among 516 patients with a recent hospitalization who subsequently developed venous thromboembolism, fewer than half (42.8%) had been given anticoagulant prophylaxis during their hospitalization, while 16.9% received only non-pharmaceutical prevention. Of these patients, only three of five (59.7%) had received any form of therapy (drug or mechanical) while hospitalized.
Because most of the cases occurred within 29 days of hospital discharge (and 41% within 14 days), it is not unreasonable to assume that some of these cases might have been prevented by increasing appropriate in-hospital prophylaxis, such as compression stockings, pneumatic compression devices, and, in high-risk patients, anticoagulants, the researchers said.
Discussing the study's limitations, the researchers noted that, as in any observational study, the chart study could have missed some cases among patients who seek care outside the study area. Furthermore, documentation of these conditions came from medical records, leaving the possibility of over- or underestimation.
Further characterization of this high-risk patient profile in additional observational studies will generate subsequent investigations that will ultimately reduce the number of these failures, the researchers concluded.
A meta-analysis published in the same issue found that both unfractionated heparin and low molecular weight heparin reduced the risk of thromboembolism in hospitalized medical patients.
When compared directly with unfractionated heparin, low molecular weight heparin was associated with a 32% lower risk of deep vein thrombosis (RR, 0.68), said Henry Krum, M.B.B.S., Ph.D., of Monash University in Melbourne, Australia, and colleagues.
But they found no difference between the two agents in the risk of bleeding or thrombocytopenia.
The researchers' analysis of 36 randomized controlled trials compared more than 48,000 hospitalized medical patients given unfractionated heparin or low molecular weight heparin with a control or with each other.
Unfractionated heparin (5,000 units three times daily) was more effective than the same dosage twice daily in preventing deep vein thrombosis (risk ratio [RR], 0.27; 95% CI, 0.20-0.36; versus RR, 0.52; 95% CI, 0.28-0.96).
Compared with the controls, unfractionated heparin was associated with a reduced risk of both deep vein thrombosis (RR 0.33; CI, 0.26-0.42) and pulmonary embolism (RR, 0.64; CI, 0.50-0.82).
This was also true for low molecular weight heparin (RR,0.56; CI, 0.45-0.70; and RR, 0.37; 95% CI, 0.21-0.64, respectively).
However, neither drug reduced mortality, the researchers reported.
"I predict that preventing outpatient venous thromboembolism will be the 'hot button' issue in 2008," said Samuel Z. Goldhaber, M.D., of Harvard, in an editorial. "We must start collecting relevant data at the time of hospital discharge so that we can provide these vulnerable patients with proper and comprehensive venous thromboembolism prophylaxis."
Proper prophylaxis requires evidence-based measures applied according to protocols used in randomized controlled trials, he said. For pharmacological prophylaxis, this means ordering the right dose of the right medication at the right time for the proper duration (which may span the hospitalization and the early period after hospital discharge).
Breaking down artificial barriers between outpatient and inpatient prophylaxis are vital first steps, Dr. Goldhaber concluded.
Dr. Spenser reported no financial conflicts. His study was supported by a grant from the National Heart, Lung, and Blood
Institute.
Dr. Krum reported no financial conflicts. His study was supported by a Centre of Clinical Research Excellence grant from the National Health and Medical Council of Australia.
Dr. Goldhaber reported no financial conflicts.Additional source: Archives of Internal MedicineSource reference: Spencer FA, et al "Venous Thromboembolism in the Outpatient Setting" Arch Intern Med. 2007; 167: 1471-1475. Additional source: Archives of Internal MedicineSource reference: Wein L et al "Pharmacological Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients" Arch Intern Med. 2007; 167: 1476-1486.
Goldhaber SZ "Outpatient Venous Thromboembolism: A Common But Often Preventable Public Health Threat" Arch Intern Med. 2007; 167: 1451-1452.

Risk for Venous Thromboembolism High After Hospital Discharge

Laurie Barclay, MD
July 13, 2007 — A high proportion of patients are at risk for venous thromboembolism (VTE) after hospital discharge, according to the results of a study reported in the July issue of the American Journal of Hematology.
"Our findings suggest that each year, almost one-third of hospitalized patients are at risk of VTE," lead author Frederick Anderson, MD, from the University of Massachusetts Medical School, Worcester, says in a news release. "This highlights the magnitude of the US public health risk posed by this potentially preventable condition."
The objective of this study was to estimate the number of inpatients in US acute-care hospitals who were at risk for VTE, using criteria established by the Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic and Thrombolytic Therapy guidelines for VTE prevention.
Using the 2003 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project, the investigators identified patients undergoing major surgery who were over 18 years of age and had a length of hospital stay of 2 days or more, as well as medical patients 40 or more years of age with a length of hospital stay of 2 or more days. ACCP guidelines were used to estimate the number of surgical and medical patients who were at risk of developing VTE.
Of an estimated 38,220,659 discharges in 2003, 7,786,390 (20%) were surgical inpatients. Of these, 44% were at low risk, 15% were at moderate risk, 24% were at high risk, and 17% were at very high risk for VTE.
Of the remaining 15,161,586 medical patients, 7,742,419 (51%) met ACCP criteria for risk for VTE. Overall, more than 12 million patients (31% of US hospital discharges in 2003) were at risk for VTE.
"Given the existence of internationally-accepted evidence-based guidelines for prevention of VTE, research is required to establish if this patient population is receiving recommended VTE prophylaxis," the authors write.
Study limitations include inability to determine whether or not the at-risk patients did indeed receive VTE prophylaxis and whether antithrombotic therapies, when used, were given appropriately.
"This large number of inpatients at risk for VTE provides support for developing and monitoring compliance with hospital protocols and national guidelines for VTE prevention," the authors conclude. "Furthermore, based on the large number of patients at risk, our data add strength to the argument that VTE prevention should be high on the list of priorities when health care policies are being formed."
Sanofi-Aventis supported this study.
In an accompanying editorial, Samuel Z. Goldhaber, MD, from Harvard University and Brigham and Women's Hospital in Boston, Massachusetts, praises this study for its significant contribution toward raising awareness of VTE and thereby improving prophylaxis for hospitalized patients.
"VTE risk does not simply evaporate when patients are discharged from hospitals," Dr. Goldhaber says. "Anderson and his group have defined a broad 'base of the iceberg' of danger. However,
the fundamental problem is even more profound and goes beyond the millions of hospitalized patients annually that they have identified."
Am J Hematol. Published online July 13, 2007.

WHO Report: Risk for Thromboembolism on Long Plane Rides Is 1 in 6000

The risk for venous thromboembolism approximately doubles after a plane flight lasting at least 4 hours but is still low, about 1 in 6000, according to WHO researchers.


Their report, released online, is based largely on three epidemiologic studies and two pathophysiologic studies.


Among the findings:


• The risk also increases with other forms of travel — such as by car, bus, or train — where riders sit immobile for long periods.


• The risk remains elevated for 2 months after the trip.


• The risk is also increased by obesity, use of oral contraceptives, presence of the factor V Leiden mutation, and extremes of height (above 6.2 or below 5.2 feet).