Daniel M Keller, PhD

July 26, 2017

BERLIN, GERMANY — Treatment of venous thromboembolism (VTE) varies widely, reflecting the broad heterogeneity among patients and underlining the need for individualized therapy, a new observational study shows[1].

Investigators presented the first results from the Global Anticoagulant Registry in the Field–Venous Thromboembolism (GARFIELD-VTE) of 10,677 patients with a confirmed diagnosis of VTE enrolled at 415 study sites in 28 countries in the Americas, Europe, Africa, the Middle East, and Asia here at the International Society on Thrombosis and Hemostasis 2017 Congress.

The registry consists of two cohorts of approximately 5000 patients each at sites considered representative of national VTE care settings.

Recruitment for the two groups began 1 year apart to compare any changes in VTE management. The original intention was to have them separated by more time, but recruitment occurred faster than anticipated.

Dr Walter Ageno (University of Insubria, Varese, Italy) presented early findings from the GARFIELD-VTE registry during a news briefing held in conjunction with the congress. He said in the short time frame between the two cohorts the standard of treatment has changed.

"Now, about 50% of patients are treated with direct oral anticoagulants [DOACs], so doctors have really changed their practice," he said. About 15% are receiving only low-molecular-weight heparin, usually patients with cancer, and about 40% are still receiving vitamin K antagonists (VKAs). Of the 50% of patients on DOACs, half of them have an initial period of heparin, and half are on a DOAC from the beginning.

One question is which patients doctors chose for DOACs. "We observed that doctors are not using these drugs in patients with cancer, or seldom, especially if cancer is active, and the reason is there are no sufficient data in this population," Ageno said. The first such studies are anticipated to be published next year. Also, patients with previous bleeding were found to be treated with more traditional anticoagulants.

"Patients with a deep vein thrombosis are more likely to receive the new drugs orally from the beginning while doctors still rely on administering parenteral agents — heparins — in patients with pulmonary embolism," he said, again, mainly because of a lack of sufficient evidence of the use of other agents in the higher-risk population.

Real-world Findings

With a variety of new anticoagulant drugs entering practice, an aim of the registry is to satisfy the "real need for doctors to see how these new drugs perform in the so-called real world" in an unselected patient population, Ageno said.

These sorts of studies are also requested by regulatory agencies after drug approval, he noted. Participants will be followed for 3 years to get information on long-term outcomes.

Overall, the prospective registry will aim to describe the acute, subacute, and extended duration of anticoagulation management and the clinical and economic outcomes of patients treated in real-world settings.

Patients were eligible if they were assessed within 30 days of VTE diagnosis. The study will follow patients for 36 months with a possible 2-year extension. Enrollment was between May 2014 and January 2017.

Ageno said the median age in the registry is 60 years; 15% of patients have underlying cancer, as "cancer is one of the most important provoking factors for thrombosis"; and 35% of patients had transient risk factors for VTE. "We also have about 45% to 50% of patients with unprovoked venous thrombosis. We don't know why the disease has occurred," he said.

Two-thirds of events were deep venous thrombosis (DVT), and one-third were pulmonary embolism (PE).

In an abstract session, Ageno described the baseline characteristics and management of the enrolled patients. Most commonly, they were treated in care settings of vascular medicine (44.8%), internal medicine, including hematology and intensive care (43.4%), followed by cardiology (5.5%), primary care (3.7%), and emergency medicine (2.5%).

Patients were evenly divided between the sexes, had a median age of 60.2 years (interquartile range 46.1–71.7 years), and were predominantly white (69.1%), followed by Asian (19.6%) and black (4.6%).

A DVT occurred in 61.7% of the patients, and 38.3% had PE with or without a DVT. DVT sites included the arm, leg, vena cava, and atypical sites. PEs were fairly evenly distributed at about 30% each in the main, lobar, and segmental pulmonary arteries, with about 10% in subsegmental arteries.

Fifteen percent of the participants had a previous VTE, 9.2% had active cancer, 6.2% had a history of cancer, and 6.0% had a family history of VTE.

Just over one-third (37.5%) of the VTEs were provoked by transient risk factors during the previous 3 months. Topping the list of transient causes were surgery (12.5%) and hospitalization (12.0%), followed by limb trauma, acute medical illness, long-haul travel, pregnancy, oral contraception, and hormone-replacement therapy.

Far and away the most common diagnostic modality for DVT was compression ultrasonography (95.5%). In one-quarter of cases D-dimer assay was used. Assessment for PE included any CT (91.8%), biomarkers including D-dimer (16.3%), echocardiography (14.2%), and ventilation perfusion scan (10.4%).

DOACs were prescribed for about half of patients with VTE overall in the first 30 days after diagnosis, whether with DVT or PE. However, patients with PE were more likely to receive parenteral treatment initially.

Therapy in the first 30 days consisted largely of anticoagulants only (85.9%). "Thirty percent of patients received what we had called for many years 'standard of treatment,' that is, parenteral anticoagulants followed by a vitamin K antagonist," Ageno told conference attendees during his presentation. Twenty-five percent received a parenteral anticoagulant and a DOAC, and 14% a parenteral anticoagulant only. "The 29.6% receiving an oral anticoagulant consisted of 25% on a DOAC only and 4.6% on a VKA only," he said.

Other approaches for VTE in the first 30 days were compression only or no therapy (9.4%) and a thrombolytic with or without anticoagulant or surgical/mechanical treatment with or without anticoagulant (4.7% combined).

The type of anticoagulant used was very similar for DVT and for PE with or without DVT, except that there was greater use of parenteral anticoagulant plus DOACs for PE (33.7%) than for DVT alone (19.9%).

In the case of cancer, 56.6% of patients with active cancer and 31.7% of those with a history of cancer received a parenteral anticoagulant alone.

Expanding on the findings of cancer in this early presentation of the GARFIELD-VTE registry, coauthor Alexander Turpie (McMaster University, Hamilton, ON) commented to theheart.org | Medscape Cardiology that within 6 months of a VTE diagnosis there was "a substantial number of people who developed cancer, and this is something we'll need to look into, whether detected by a screening test or whether actually clinically evident cancers that just became apparent during treatment."

Half the deaths in the study were cancer related and were highest in the first month after VTE diagnosis. "So I think that the message is we really have to look at a holistic approach to the management of these patients and make sure there are no other treatable diseases associated with the occurrence of DVT," he said.

When asked whether VTE may have been an early sign of hypercoagulability caused by an underlying cancer that was not yet clinically apparent, Turpie responded, "Yes, I suspect that is the case. As you saw in the presentation by Ageno, 10% of the patients had active cancer, and another I think it was 8% or 9% had a history of cancer. And then subsequently they saw additional cancers that were observed that may of course have been there at the time of diagnosis but were just not detected."

He said a big question is whether to screen people for cancer who present with VTE. Cancer raises the risk of VTE four- to sevenfold by various estimates, and VTE has been proven to raise the likelihood of death in cancer patients two- to sixfold. Approximately 20% of all VTE cases occur in people with cancer, and VTE is found in up to 50% of autopsies of patients with cancer.

"A study like GARFIELD will actually allow us to look at the characteristics of the patients who develop cancer so that we can perhaps tailor our investigation to the patients with the highest risk," Turpie said.

Dr Wolfram Ruf (Johannes Gutenberg University, Mainz, Germany), who moderated the news conference in which Ageno spoke, commented to theheart.org | Medscape Cardiology that it is important to look at how anticoagulants are being used in the real world after introduction of the new DOACs.

"The GARFIELD registry really looks in very different countries, in different settings, and it really has a good quality control of the data input, and it's a prospective registry, not retrospective," Ruf said. "I think this is a registry that will provide very insightful information on the actual use of anticoagulants in real populations, in the elderly and so forth, where obviously the balance between anticoagulant therapy and bleeding risk is kind of higher than in the typical trial population," so "this is an important follow-up on the clinical trials that showed the efficacy and safety of these drugs."

The GARFIELD-VTE registry is an independent academic research initiative sponsored by the Thrombosis Research Institute (London, UK) and supported by an unrestricted research grant from Bayer (Berlin, Germany). Ageno has research funding from Bayer and is on the advisory boards of Bayer, Daiichi Sankyo, Boehringer Ingelheim, Portola, and Sanofi. He has received honoraria from these companies as well as from Stago, CSL Behring, and Aspen. Ruf had no relevant financial relationships.  Turpie is on the GARFIELD-VTE steering committee and is a coauthor of the GARFIELD-VTE presentation.

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