Results from a recent French study based on data from clinical practice indicate that vitamin K antagonists and low-molecular weight heparin are more effective than aspirin in preventing clots during myeloma treatment with the immuno­modu­la­tory drugs thalidomide or Revlimid.

Specifically, 7 percent of patients receiving aspirin developed blood clots, compared to 3 percent of patients receiving low-molecular weight heparin and 0 percent receiving a vitamin K antagonist such as warfarin (Coumadin).

Interestingly, the rate of blood clot formation was lowest among patients with the highest risk of developing blood clots, which the researchers speculate is due to the fact that high-risk patients are more often pre­venta­tively treated with vitamin K antagonists and low-molecular weight heparin.

“Blood clot formation is a frequent and serious side effect related to the use of immunomodulatory drugs in myeloma patients. Therefore, preventive treatment should be compulsory in myeloma patients treated with immunomodulatory drugs regardless of risk factors for clot formation,” the investigators write in their paper.

Based on their findings, the researchers conclude that aspirin is “not considered an efficient treatment” for preventing blood clots. They suggest that physicians prescribe low-molecular weight heparin or vitamin K antagonists to patients at high risk for clot formation.

The results from the current study also show that the frequency of blood clots remained high during the first 12 months of treatment with thalidomide and Revlimid, which according to the investigators may indicate that patients are at risk of developing blood clots as long as they are receiving immunomodulatory drugs.

“Thus, myeloma patients should be maintained on [blood clot prevention] as long as the increased blood clot risk is present, that is while remaining on [an immunomodulatory drug]-based regimen,” conclude the investigators.

Background

Immunomodulatory agents (IMiDs) are a class of drugs that work by inducing the patient’s immune system to attack and destroy myeloma cells. IMiDs include thalidomide (Thalomid), Revlimid (lenalidomide), and Pomalyst (pomalidomide, Imnovid).

Previous studies have shown that IMiDs, particularly in combination with dexamethasone (Decadron), increase a patient’s risk of developing blood clots in veins (a serious condition called venous thromboembolism). Blood clots often form in deep veins and may become life-threatening if they break off and lodge in arteries in the lungs.

In the Unites States, the prescribing information for all IMiDs contain warnings that these drugs increase the risk of blood clots. Patients and physicians are advised to consider the use of treatments for the prevention of blood clots. Patients who receive IMiD-based treatment therefore often receive blood-thinning agents such as aspirin, low-molecular weight heparin, or a vitamin K antagonist. In the United States, the most widely used vitamin K antagonist is warfarin.

In the current study, termed MELISSE, French researchers aimed to determine how frequently blood clots occurred during IMiD-based treatment of myeloma. They also sought to identify risk factors linked to increased risk of clots and to compare the effectiveness of different anti-clotting agents for the prevention of blood clot formation.

Study Design

A total of 524 patients from 52 centers in France participated in this study. The study was non-interventional in nature, meaning that the researchers simply collected and analyzed ‘real-life’ data from patients as they underwent treatment in the clinic (not in clinical trials).The median age of participants was 71 years, with 65 percent of patients being above the age of 65 years.

Overall, 64 percent of patients received Revlimid-based therapy and 36 percent received thalidomide-based therapy.

About 39 percent of patients had received no prior treatment, and the other 61 percent had received one or two previous lines of therapy.

The investigators followed up with patients at four months and 12 months from the start of treatment.

Study Results

Trends In The Prescription Of Anti-Clotting Agents

First, the researchers investigated if the perceived risk of clot formation influenced physicians’ choice of anti-clotting agents.

Before beginning IMiD treatment, all patients were evaluated for the risk of blood clot formation using current guidelines. Classical risk factors for clot formation include patient-related factors, such as a personal/family history of blood clots, surgery, obesity, and lack of mobility, as well as myeloma-related factors, such as increased thickness of blood and the placement of a catheter into a large vein.

Based on these risk factors, 47 percent of patients were classified as low-risk, 39 percent as intermediate-risk, and 14 percent as high-risk.

Overall, 85 percent of patients received treatment for the prevention of blood clots, including 59 percent who received aspirin, 17 percent low-molecular weight heparin, and 9 percent a vitamin K antagonist.

The majority of low-risk (70 percent) and intermediate-risk (58 percent) patients were treated with aspirin. In comparison, most high-risk patients received low-molecular weight heparin (43 percent) or vitamin K antagonists (34 percent).

To the investigators’ surprise, 16 of patients did no receive any treatment for the prevention of blood clots. The majority of patients who received no preventive treatment fell in the low-risk or intermediate-risk category.

The researchers also performed statistical analyses to determine what other factors in addition to the assessed risk of clotting significantly influenced the physicians’ decisions to prescribe preventative treatment with anti-clotting agents.

They found that physicians’ choices were most often influenced by the patient’s risk of clotting, followed by the patient’s time since myeloma diagnosis, heart function, family/personal history of blood clots, and dexamethasone therapy.

Blood Clot Formation During IMiD-Based Treatment

Analysis of the side effects of IMiD-based treatment showed that a total of 6 percent of patients developed blood clots, with 4 percent developing clots in the deep veins and 2 percent developing clots in arteries in the lungs.

According to the researchers, the risk of clot formation was previously thought to be particularly high during the first four months to six months of IMiD-based treatment. However, results from the current study show that the frequency of blood clots was not significantly different between the first four months and next eight months of treatment.

“IMiDs are associated with an increased risk of clot formation in myeloma patients beyond the first six months of the IMiDs course. Therefore awareness on clotting risk should persist at any time during IMiDs treatment,” the investigators note in their paper.

Clot formation was seen in all risk categories, with 7 percent of low-risk patients, 6 percent of intermediate risk patients, and 3 percent of high-risk patients developing clots.

The researchers explain that high-risk patients may have been less likely to develop blood clots due to ‘better and optimized’ preventive regimens with low-molecular weight heparin and vitamin K antagonists.

About 7 percent of patients on aspirin, 3 percent of patients on low-molecular weight heparin, and 8 percent of patients who did not receive preventative treatment developed blood clots.

However, no blood clot formation was observed in patients receiving vitamin K antagonists. In addition, vitamin K antagonists were found to be significantly more effective than aspirin in this study.

Among patients who experienced blood clots in the lungs, 82 percent had received aspirin and the others had received no anti-clotting medication. No patient on low-molecular weight heparin or vitamin K antagonists experienced blood clots in the lungs.

When patients on thalidomide-based and Revlimid-based regimens were analyzed separately, the results showed that more patients on thalidomide-based treatment (8 percent) developed blood clots, as compared to patients receiving Revlimid-based treatment (5 percent).

Analysis Of Risk Factors For Clot Formation

Further mathematical analysis revealed additional risk factors linked to blood clot formation. Patients with a shorter time from diagnosis to IMiD treatment were found to be at higher risk for clot formation. Treatment with recombinant erythropoietin, a hormone that boosts red blood cell counts, also significantly increased the risk of clot formation.

Treatment with aspirin did not reduce a patient’s risk of developing blood clots, compared to no preventative treatment, and patients treated with aspirin were nearly twice as likely to develop blood clots as patients treated with low-molecular weight heparin or vitamin K antagonists.

The investigators also analyzed factors that increased the risk specifically for deep vein clots, as compared to clots in the lung. They found that both gender and smoking habits influenced the risk for deep vein clots. Men were more likely to develop deep vein clots than women, and smokers were more likely to develop them than non-smokers.

The researchers could not draw any definitive conclusions about the impact of clot formation on survival.  However, based on observations that only 4 percent of patients who died developed blood clots, they note that blood clot formation was unlikely to significantly impact survival in this study.

For further information, please see the study in Thrombosis and Haemostasis (abstract).