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Warfarin alternative trialled

Scientists have developed a daily pill that ‘slashes the risk of stroke by more than a third’, according to the Daily Express. The findings come from a study on people with an increased risk stroke due to atrial fibrillation (AF), a form of irregular heartbeat.

The study compared a new pill, called dabigatran, with warfarin, the blood-thinning drug that people with AF commonly take to reduce their risk of stroke. The effects of warfarin are difficult to control and people who take it need regular monitoring to reduce their risk of haemorrhages (bleeding). The study found that those who took dabigatran reduced their risks of both stroke and systemic embolism (a clot that forms in the heart and then travels around the body) by 34%. The pill also offered less risk of bleeding than warfarin.

This robust study was published in the New England Journal of Medicine and says the results show promise for dabigatran, which could be as effective as warfarin at reducing the risk of stroke and related events while also reducing the risk of major bleeding and the need for regular monitoring sessions. However, the results show that dabigatran may be associated with side effects such as gastrointestinal symptoms, which means it may be less suitable for some patients. As the Daily Express coverage says, abigatran is already licensed for use in people having hip and knee replacement surgery, but regulatory bodies will need to review available evidence before it can be licensed for people with AF.

Where did the story come from?

Dr Stuart J Connolly and colleagues from McMaster University in Canada and other international research centres carried out this study. The study was funded by Boehringer Ingelheim, the manufacturer of dabigatran. The Population Health Research Institute in Canada independently managed the study database and performed the main data analyses, and an international steering committee (including the study’s financial sponsors) was responsible for the design, conduct and reporting of the study. The study was published in the peer-reviewed New England Journal of Medicine.

What kind of scientific study was this?

This was a randomised controlled trial called the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. This study looked at people with a heart condition called atrial fibrillation (AF), which increases the risk of stroke and can be treated using the anticoagulant drug warfarin.

The effects of warfarin are difficult to control and patients need regular health checks to monitor the level of anticoagulation being achieved. The authors of the study report that this means there is a need for new anticoagulant drugs that are safe, effective and convenient to use. Their study assessed one such drug, called dabigatran. The study (called a non-inferiority trial) was designed to test whether dabigatran was at least as good as warfarin in preventing strokes and related events.

The researchers recruited 18,113 people, from 44 countries, who had AF (a type of irregular heartbeat) and at least one other risk factor for stroke. The other risk factors included:

  • previous stroke or mini-stroke,
  • poor heart function (a left ventricular ejection fraction less than 40%),
  • recent heart failure symptoms (New York Heart Association class II or higher heart-failure symptoms within the past six months), or
  • being at least 75 years old, or 65 to 74 years old with diabetes mellitus, coronary artery disease or high blood pressure.

The researchers excluded people with a severe heart valve disorder, who had any stroke in the past two weeks or a severe stroke in the previous six months, any condition that increased the risk of bleeding, active liver disease, signs of poor kidney function or who were pregnant.

The participants were randomly assigned to receive either 110mg or 150mg of dabigatran twice a day, or warfarin at a dose that could be adjusted to provide a pre-specified level of anti-clotting activity. This warfarin dosage was adjusted in relation to this level of anti-clotting activity, which is assessed using a measure called the ‘international normalised ratio’ or INR. An INR of two or three was the target in this study and this was assessed in the warfarin group at least once a month.

People taking dabigatran were blinded to what they were taking, but those who received warfarin were not. Participants were followed up for an average (median) of two years to see what proportion in each group experienced a stroke or a systemic embolism (where a clot forms in the heart but breaks apart, causing the pieces to move around the body). The researchers also looked for side effects of the drugs, including major bleeding and effects on liver function.

All outcome events (for example, stroke or major bleeding) were assessed by two independent investigators, who were blinded to the participants’ assigned treatment. To detect possible unreported events, the participants filled out regular questionnaires on potential symptoms and the researchers evaluated adverse-event and hospitalisation reports.

In a non-inferiority trial, researchers set a level at which they would decide that the new drug might be inferior to the old drug. In this case, the researchers decided that they needed to be at least 97.5% confident that dabigatran would not increase the risk of stroke or systemic embolism by 1.46 times or greater compared with warfarin.

What were the results of the study?

The average age of the participants was 71 years old. Around 64% were men and about 50% had received long-term treatment with a class of anticoagulant drugs called ‘vitamin K antagonists’, which include warfarin.

During the study, 1.69% of people taking warfarin experienced a stroke or systemic embolism each year, compared with 1.53% a year in the group taking 110mg of dabigatran and 1.11% a year in the group taking 150mg of dabigatran.

This meant the lower dose of dabigatran was as good as warfarin for preventing stroke and embolism events (relative risk [RR] 0.91, 95% confidence interval [CI] 0.74 to 1.11), and the higher dose of dabigatran was better than warfarin for preventing these events (RR 0.66, 95% CI 0.53 to 0.82).

Other findings were:

  • The lower dose of dabigatran was associated with a significantly lower risk of major bleeding (2.71% of patients a year) than warfarin (3.36% of patients a year). There was no significant difference between the higher dose of dabigatran (3.11% of patients a year) and warfarin.
  • Both doses of dabigatran reduced the risk of haemorrhagic stroke compared with warfarin (0.12% a year with lower dose dabigatran and 0.10% a year with higher dose dabigatran compared with 0.38% a year with warfarin).
  • The annual death rate was slightly lower in the dabigatran groups than in the warfarin group, but this difference was not statistically significant: 4.13% a year with warfarin compared with 3.75% a year with lower dose dabigatran and 3.64% a year with higher dose dabigatran.

What interpretations did the researchers draw from these results?

The researchers concluded that the lower dose of dabigatran (110mg twice daily) was as good as warfarin at reducing the risk of stroke and systemic embolism in people with AF, and was associated with a reduced risk of major haemorrhage.

The higher dose of dabigatran (150mg twice daily) reduced the risk of stroke and systemic embolism in people with atrial fibrillation more than warfarin, but was associated with similar rates of major haemorrhage.

What does the NHS Knowledge Service make of this study?

This researchers used a robust study design to compare dabigatran and warfarin. Their results show promise for this new drug, which may produce a similar level of risk reduction for stroke and related events while reducing the risk of major bleeding and the need for such frequent monitoring. There are a number of points to note:

  • The authors say that lack of blinding of people taking warfarin might bias outcomes but that they took steps to avoid this by using independent blinded assessment of outcome.
  • Dabigatran (particularly the higher dose) seemed to be associated with a higher risk of heart attack and a higher risk of gastrointestinal bleeding than warfarin. These side effects may mean that dabigatran may be less suited to some patients than others.
  • The proportions of people who had stopped taking their medication after one and two years of follow up were higher in the dabigatran groups than the warfarin group. At one year about 15% of participants in the dabigatran groups had stopped compared with 10% in the warfarin group. At two years 21% in the dabigatran groups had stopped compared with 17% in the warfarin group. Serious adverse events were a more common reason for discontinuation in the dabigatran groups (2.7%) than with warfarin (1.7%). Discontinuation due to gastrointestinal symptoms was also more common with dabigatran (about 2% in both groups) than with warfarin (0.6%).

As these results were obtained in people with AF plus another risk factor for stroke, they may not be indicative of what would be seen in other groups. For example, results may be different among patients who were excluded from the study, such as those with recent strokes or at increased risk of bleeding.

Dabigatran has the advantage that, unlike warfarin, it does not need to be closely monitored using blood tests. This means that the drug is likely to be preferred by patients. The advantages and disadvantages of this drug will be of great interest to people who are taking anticoagulant medicines such as warfarin indefinitely, particularly those in hard-to-treat groups such as the very old.

Links to the headlines

Alternative drug to warfarin reduces risk of stroke. The Times, August 31 2009

New stroke pill Pradaxa on its way. Daily Mirror, August 31 2009

NEW PILL CUTS RISK OF STROKE. Daily Express, August 31 2009

Links to the science

Connolly SJ, Ezekowitz MD, Yusuf S et alDabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM August 30 2009

Gage B. Can We Rely on RE-LY?. NEJM August 30 2009

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