A new drug will slash risk of strokes according to the Daily Express . The newspaper says that the anti-clotting drug dabigatran is as safe and effective at treating deep vein thrombosis as the traditional drug warfarin.
The reports are based on a trial that compared dabigatran to warfarin in people who have blood clots in the veins of the leg or lung (venous thromboembolism). The study found that dabigatran and warfarin work equally well to prevent clots, but that there is a slightly reduced risk of bleeding problems with dabigatran compared with warfarin treatment. It did not directly look at the risk of strokes.
Warfarin can have a number of side effects and has to be carefully prescribed and monitored by a doctor, so there is interest in finding potential alternatives. Dabigatran is already licensed in the UK for preventing clots in people having hip or knee replacement surgery. It is not yet licensed for use in patients who already have a venous thromboembolism, and this study will be important in applying for such licensing.
Where did the story come from?
This research was conducted by Dr Sam Schulman and colleagues from the RE-COVER study group, and was funded by Boehringer Ingelheim, the firm that markets dabigatran. Members of Boehringer Ingelheim designed and conducted the study, which they analysed with a steering committee that vouched for the accuracy and completeness of the data and the analyses.
The research was covered by the Daily Express and the Daily Mail . The Mail emphasised the problems with warfarin, saying it requires close monitoring due to difficulties in precisely controlling its dosage. The Express correctly reports the main result of the study, that dabigatran and warfarin are equally effective in preventing recurrent blood clots.
The Express also focuses on the lower risk of bleeding with dabigatran, with a headline suggesting that dabigatran reduces the risk of strokes. While blood clots are associated with stroke, and other studies have tested the drug in people at risk of stroke, this current study did not specifically look at outcomes of stroke. The Mail also misreports the number of patients in the study, suggesting that 25,000 patients were involved rather than the actual amount of around 2,500.
What kind of research was this?
This study was a double-blind randomised-controlled trial (RCT) that investigated how well the newer drug dabigatran prevented the recurrence of blood clots compared to warfarin, the standard blood-thinning drug.
This type of study is the best way to assess how effective a new drug is compared to the best existing drug. This particular trial was a special kind of RCT called a non-inferiority trial, which means that the researchers were assessing whether the new drug was at least as good as warfarin.
Warfarin and dabigatran tablets look distinctly different to one another, so the researchers included a double dummy phase in which the two groups of participants received both an active drug and a placebo pill that looked like the other drug. This was so that the participants and the researchers would not know which active treatment they were receiving. This is the best way to ensure that patients’ or researchers’ personal beliefs about the effects of treatment do not affect the outcome or how the outcome is perceived.
What did the research involve?
The researchers recruited participants from 29 countries. They selected 2,539 who had either symptomatic deep vein thrombosis (DVT) of the legs, or a pulmonary embolism (blood clots affecting the blood vessels of the lungs). All participants had to be considered appropriate candidates for a six-month course of anticoagulant therapy. The study also excluded people who had experienced their symptoms for more than 14 days, had recent cardiovascular disease, were at a high risk of bleeding, had abnormal liver function or had a life expectancy of less than six months.
Before starting the trial patients were treated with the injected anticoagulant heparin. The participants were then randomly assigned to receive either warfarin or dabigatran for six months. There were 1,266 participants in the warfarin group and 1,273 participants in the dabigatran group.
They were assessed for blood clot symptoms, bleeding, abnormal liver function and abnormal heart function once a week for the first month and then once a month for the remaining five months of the study. The researchers also recorded details of any patient deaths.
Before analysing the data, the researchers decided that dabigatran would be considered to be as effective as warfarin if it was not likely to increase the risk of symptomatic venous thromboembolism or death associated with venous thromboembolism by more than 3.6%.
What were the basic results?
In this study some of the participants did not complete the six-month treatment or were assessed before the end of the observation period. This was mostly due to adverse events, although the proportion of participants who did not complete the study was similar in both treatment groups (16% in the dabigatran group and 14.5% in the warfarin group).
The researchers found that a similar proportion of the warfarin and dabigatran group experienced a recurrence of clots or death from recurrent clots: 2.4% in the dabigatran group and 2.1% in the warfarin group, a difference of +0.4% (95% confidence interval [CI] -0.8% to +1.5%; hazard ratio [HR] 1.10, 95% CI 0.65 to 1.84).
As the difference in clot risk was less than the 3.6% margin set by the researchers, the drugs were considered to be similarly effective at preventing this outcome.
The risk of having a major bleed in the dabigatran group and the warfarin group was similar, at 1.6% and 1.9% respectively (HR 0.82, 95% CI 0.45 to 1.48).
However, when the analysis included both major bleeds and clinically relevant non-major bleeds, those in the dabigatran group were less likely to have bleeds than those in the warfarin group (HR 0.63, 95% CI 0.47 to 0.84).
Within the two treatment groups a similar proportion of participants had adverse events (dabigatran 66.3%, warfarin 67.6%). However, the proportion of participants with indigestion problems was higher in the dabigatran group (3.1%) compared to the warfarin group (0.7%; p less than 0.001).
How did the researchers interpret the results?
The researchers concluded that their trial “provides data to support dabigatran as a fixed-dose oral treatment for acute deep vein thrombosis and pulmonary embolism”. They said that the decrease in non-clinical bleeds with dabigatran is an important issue since management of bleeds is time-consuming and costly and because bleeding is the major reason behind patients’ perception that warfarin treatment decreased health and quality.
They also add that “dabigatran is a far more convenient drug than warfarin because it has no known interactions with foods, and minimal interactions with other drugs and therefore does not require routine blood-coagulation testing”.
The anticoagulant dabigatran is already licensed as an alternative treatment to warfarin in certain cases. This study suggests that it works equally well to prevent the recurrence of blood clots in people who have had a clot in their leg or lung. The study also suggests that both treatments have an adverse effect of causing bleeding, but there is less risk of general bleeds with dabigatran.
This was a well-conducted study. One potential limitation that the authors highlight is that they treated patients with the injected anticoagulant heparin for varying lengths of time before starting treatment with dabigatran or warfarin. However, the researchers say that other studies have shown that the length of time for which a patient receives heparin treatment does not affect how well subsequent anticoagulation therapies work. They also suggest that further studies should be conducted in people with different characteristics, as 95% of the study’s participants were white and they had an average age of 55 years.
Based on this study, dabigatran may be a similarly effective alternative to warfarin for people with venous thromboembolism, and it could be more convenient than treatment with warfarin. Dabigatran is currently licensed in the UK for preventing clots in people having hip or knee replacement surgery, but it is not yet licensed for use in patients with venous thromboembolism. This study will be important in applying for such licensing.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
Daily Mail, 7 December 2009
Links to the science
The New England Journal of Medicine 2009; 361