What was the research about?
People with cancer have a higher-than-normal risk for blood clots. These blood clots form in the veins, and they can cause pain and lead to hospital stays or even death.
Blood thinners can prevent clots but may cause problems such as severe bleeding. Also, most patients who use older blood thinners must inject them each day using needles; they may also need frequent blood tests. Since 2012, patients can take newer blood thinner pills by mouth. These medicines do not require regular blood tests.
In this study, the research team wanted to learn whether the newer pills were worse or no worse than the injectable blood thinners at preventing future blood clots among patients with cancer who had a recent clot.
What were the results?
After six months, the two types of blood thinners worked about the same to prevent clots. However, about 71 percent of patients taking the newer blood thinners kept taking their assigned medicine compared with 59 percent of patients on the older injectable blood thinners.
Patients taking newer blood thinners and patients taking older blood thinners didn’t differ in:
- Cases of bleeding
- Serious side effects
- Quality of life
- Reported burden and benefits of taking the medicine
Who was in the study?
The study included 638 adults with cancer who had a blood clot within the last month. All were receiving care at one of 67 cancer clinics across the United States. Among patients, 83 percent were White, 11 percent were Black or African American, and 5 percent were another, more than one, or unknown race; 5 percent were Hispanic. The average age was 61, and 55 percent were women.
What did the research team do?
The research team assigned patients by chance to receive either the newer or older blood thinners. The patients’ doctors could choose which type of newer or older blood thinner patients received. During the study, patients who took the older injectable blood thinners could switch to warfarin, a blood thinner taken by mouth, if they had difficulty with the injections. Patients in both groups saw their doctors as needed for care.
At the start of the study and again after six months, patients completed surveys. Surveys asked if patients were taking their medicine and about quality of life as well as the burden, benefits, and side effects of medicines. The research team also reviewed patients’ health records for other health outcomes.
Patients with cancer, patient advocates, and doctors gave input on the study design.
What were the limits of the study?
The research team didn’t recruit as many patients into the study as they had planned. Therefore, the team could not tell if one type of blood thinner was better than the other, only if one type was no worse than the other.
Future research could determine which type of blood thinner is better for preventing blood clots among patients with cancer.
How can people use the results?
Patients with cancer and their doctors can use these results when considering medicines to prevent blood clots.
To compare the safety and effectiveness of direct oral anticoagulants (DOACs) versus low molecular weight heparins (LMWHs) in preventing recurrent venous thromboembolism (VTE) among patients with cancer
|Design||Randomized controlled trial|
|Population||638 adults ages 18 and older with a diagnosis of an invasive solid tumor malignancy, lymphoma, chronic lymphocytic leukemia, or myeloma and a VTE within 30 days prior to study enrollment|
Primary: VTE recurrence
Secondary: bleeding, health-related quality of life, mortality, serious adverse events, persistence with anticoagulant therapy, medication burden and benefits
|Timeframe||6-month follow-up for primary outcome|
This pragmatic randomized controlled non-inferiority trial compared the effectiveness of DOACs versus LMWHs in preventing recurrent VTE among patients with cancer. The study also compared the effect of these medications on bleeding, mortality, serious adverse events, health-related quality of life, treatment burden, and persistence with medication therapy.
Researchers randomized patients to receive either a DOAC or an LMWH for six months. In the DOAC group, patients’ doctors could choose from one of four DOACs. Doctors determined medication dose based on package label instructions for treating VTE and patients’ weight, renal function, and anticipated medication interactions. In the LMWH group, patients’ doctors could choose from one of three LMWH injections. Patients in the LMWH group could transition to warfarin if they could not tolerate the injections. In both groups, patients visited their doctors for care as needed.
The study included 638 adults with cancer and a VTE who were receiving care at one of 67 oncology practices across the United States. Of these patients, 83% were White, 11% were Black or African American, and 5% were another, more than one, or unknown race; 5% were Hispanic. The average age was 61, and 55% were female.
At the start of the study and again three and six months later, patients completed surveys by email, mail, phone, or in person at clinic visits. Surveys asked whether patients were taking the medication and about their quality of life as well as the burden, benefits, and side effects of the medications. Researchers also reviewed patients’ medical records for clinical information. Researchers defined the non-inferiority statistical threshold to be if the upper limit of the 90% confidence interval (CI) for the six-month risk of developing VTE was less than 3% for patients receiving DOACs compared with those receiving LMWHs.
Patients with cancer, patient advocates, and doctors gave input on the study design.
At six months, DOACs were statistically non-inferior to LMWHs in preventing VTE; 6.1% of patients receiving DOACs and 8.8% of patients receiving LMWHs had a VTE (difference = -2.7; 90% CI: -6.1, 0.7). However, a higher percentage of patients receiving DOACs were still taking their anticoagulant at six months compared to patients receiving LMWHs (70.9% versus 59.4%, difference = 11.5; 95% CI: 4.1, 18.8).
The two groups did not differ significantly in bleeding, mortality, serious adverse events, quality of life, or burden and benefits of medication.
The study originally sought to determine whether one type of drug was superior to the other. Due to lower-than-expected enrollment, the research team could not determine statistical superiority of the performance of one type of drug over the other and changed their analysis to assess non-inferiority instead.
Conclusions and Relevance
In this pragmatic trial, DOACs were not inferior to LMWHs at preventing recurrent VTE among patients with cancer and had similar rates of major bleeding and death.
Future Research Needs
Future research could determine whether one type of drug is superior to the other for preventing recurrent VTE among patients with cancer.
Final Research Report
This project's final research report is expected to be available by August 2023.
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers asked why the researchers chose to close the preference cohort in which study participants had the opportunity to choose their treatment rather than be randomized. The researchers explained that they developed closing rules for the preference cohort so that entry would be closed if a large imbalance developed in participants’ choice of treatment. The researchers noted that a much larger proportion of participants in the preference cohort chose direct oral anticoagulants (DOACs) compared to those who chose usual care, creating an imbalance that could induce information loss in subsequent statistical analyses.
- The reviewers suggested that the researchers delineate how this study was a pragmatic trial which differed from industry-sponsored clinical trials. The researchers did not directly compare traditional clinical trials to pragmatic trials, but in the background section they did list the advantages of the pragmatic trial design for their specific study question.
- The reviewers noted that the report identified the primary study outcomes as recurrent venous thromboembolism (VTE) or VTE-related death within six months of treatment randomization despite the researchers acknowledging the difficulty of attributing cause of death because diagnostic procedures are rarely performed post-mortem on cancer patients with recurrent VTE. The researchers corrected the report to list only recurrent VTE based on antemortem diagnosis as a primary outcome, with all-cause mortality as secondary.
Study Registration Information
- Has Results