Tuesday April 5 2011
Ischaemic strokes occur when blood clots block the flow of blood to the brain
“Super pill cuts risk of stroke for one million Britons,” reported the Daily Mail. The news story is based on the latest results from research on the anticoagulant drug Pradaxa.
The drug is currently licensed for the prevention of venous blood clots (e.g. DVT) in people who have had hip or knee replacement surgery. A large trial in over 18,000 people in 2009 found that the drug also reduces the risk of stroke compared to warfarin in people with atrial fibrillation (AF). AF is an irregular heart rhythm that raises the risk of blood clots.
This updated research, presented at a conference in the US, looked retrospectively at the data from the 2009 trial. It found the drug had similar effects in different groups of people with AF who had other risk factors for stroke, and for different types of AF (temporary or persistent).
An application has been made to the European Medicines Authority (EMA) to extend the licence of Pradaxa for the prevention of thromboemolism (blood clots) and stroke in people with AF. If Pradaxa is found to be safe and effective by the EMA, it will potentially be available for prescription by doctors in the UK within the next few months. Its use within the NHS will be dependent on NICE guidelines that are due to be published in December.
Where did the story come from?
The study was carried out by researchers on behalf of the pharmaceutical company Boehringer Ingelheim, the manufacturer of Pradaxa. These results were presented at the American College of Cardiology’s 60th Annual Scientific session, and they were described in a press release from Boehringer Ingelheim.
The news reports focused on the number of people who could be treated with pradaxa. They accurately point out its benefits compared to warfarin in so much that it does not need monitoring and dose adjustments. The Daily Mail reported that the treatment could be available within weeks, and this could potentially happen. For the drug to be used in the UK for the treatment of atrial fibrillation it will need a European Medicines license. If Pradaxa is found to be safe and effective by the EMA it will be available to be prescribed by doctors in the UK.
The National Institute for Health and Clinical Excellence (NICE) is currently assessing Pradaxa compared with established treatments such as warfarin to prevent strokes and blood clots in people with atrial fibrillation. These guidelines are due to be published in December. The focus of this report will be to assess the effectiveness and safety of Pradaxa relative to warfarin, taking into account the cost of the drug, so that recommendations can be made for doctors to decide between treatments for their patients in the UK.
Although if approved by the EMA, this drug may be available for patients with atrial fibrillation in the UK within weeks, the NICE report in December may recommend that Pradaxa is available to a limited population. In the intervening period it is likely that health providers will have to decide at a local level whether or not to prescribe the drug.
What kind of research was this?
This was a retrospective subanalysis of the results from a randomised controlled trial called RE-LY (Randomized Evaluation of Long term anticoagulant therapy). RE-LY compared the effect of the new drug Pradaxa with warfarin for preventing strokes in people with atrial fibrillation (AF). Pradaxa is the brand name of the anticoagulant drug dabigatran. Warfarin is currently the established preventative treatment.
Both Pradaxa and warfarin stop blood clotting. People with AF have an abnormal heart rhythm and their blood is not pumped out of the heart properly. This means they have an increased risk of blood clots forming, which in turn leads to a greater risk of stroke. In 2009, findings from the RE-LY trial indicated that Pradaxa was better than warfarin at lowering the risk of stroke in patients with atrial fibrillation.
The aim of this subanalysis was to investigate whether the reduction in stroke risk with Pradaxa compared to warfarin was affected by how “at risk” the person was for stroke and the type of atrial fibrillation they had.
What did the research involve?
The original RE-LY trial recruited 18,113 patients with atrial fibrillation, and compared two doses of Pradaxa (110 mg and 150 mg) to warfarin (1, 3 or 5mg tablets). The trial measured the incidence of stroke of any type (hemorrhagic, caused by bleeding in the brain, or ischaemic, which is caused by a clot blocking a brain blood vessel) or the presence of blood clots. It also recorded side effects of the treatments.
In the first subanalysis, the researchers grouped people according to their risk factors for stroke. This test, called the CHA2DS2-VASc risk score, takes into account factors such as congestive heart failure, high blood pressure, age, previous stroke, vascular disease, diabetes and gender. The participants were put into four groups: those with a score of 0-2, 3, 4 and 5-9, with the higher scores showing a greater risk. The researchers then calculated the risk of having a stroke in those who had received 150mg Pradaxa compared to those who had received warfarin in each subgroup. For warfarin, the dose may vary as patients have to adjust their dose to maintain clotting within a target range.
In the second subanalysis, the researchers looked at the type of atrial fibrillation the participants had. The analysis only looked at people who had non-valvular atrial fibrillation (NVAF - those without heart valve disease). The NVAF participants were grouped as having:
- permanent (long-standing) atrial fibrillation
- paroxysmal (where AF terminates spontaneously)
- persistent (AF lasting beyond seven days)
What were the basic results?
Compared to warfarin, 150mg Pradaxa taken twice daily was associated with reduced stroke risk across all four of the stroke risk groups:
- Risk score 0 to 2, the Pradaxa group was 37% less likely to have a stroke relative to the warfarin group (relative risk RR 0.63)
- Risk score 3, the Pradaxa group was 39% less likely to have a stroke relative to the warfarin group (RR= 0.61)
- Risk score 4, Pradaxa group was 47% less likely to have a stroke relative to the warfarin group (RR= 0.53)
- Risk score 5-9, the Pradaxa group was 23% less likely to have a stroke relative to the warfarin group (RR= 0.61)
The confidence intervals for these results were not reported in the press release, therefore it is not clear whether Pradaxa significantly lowered the risk of stroke compared to warfarin. Such data will be included in the European licensing submission. However, all four groups taking pradaxa, from highest to lowest risk of AF, had similar benefits from the drug (comparison between risk groups in people taking Pradaxa p=0.60).
The researchers also looked at the risk of bleeding (a potential side effect of anti-clotting agents).
They found that for people in each group:
- Risk score 0 to 2, the Pradaxa group were 25% less likely than the warfarin group to have a major bleed (RR= 0.75)
- Risk score 3, the Pradaxa group 26% were less likely than the warfarin group to have a major bleed (RR= 0.74)
- Risk score 4, the Pradaxa group were 17% less likely than the warfarin group to have a major bleed (RR= 0.83)
- Risk score 5-9, the Pradaxa group were 33% more likely than the warfarin group to have a major bleed (RR= 1.33)
There was a difference between the people at highest risk of stroke (risk score 5-9) and people at lower risk in terms of having a major bleed with Pradaxa (p=0.003).
In the second subanalysis, they found that 150mg Pradaxa reduced the likelihood of stroke and blood clots relative to the warfarin group in all three atrial fibrillation subgroups:
- In the permanent AF group, the hazard ratio (HR) was 0.7 indicating a 30% decreased risk relative to the warfarin group.
- The paroxysmal AF group had a HR of 0.61, indicating a 39% decreased risk relative to the warfarin group.
- The persistent AF group had a HR of 0.64 indicating a 36% decreased risk relative to the warfarin group.
The researchers found that for the permanent AF group the rate of major bleeding events in the two populations was 3.07% per year in the Pradaxa group and 2.96% in the warfarin group.
In the paroxysmal group, the rates were 3.74% in the Pradaxa group and 3.91% in the warfarin group. In the persistent group, the rates were 3.14% in the Pradaxa group and 3.88% in the warfarin group.
There was no difference between the subtypes of atrial fibrillation in terms of stroke risk or bleeding while taking Pradaxa.
In the original RE-LY trial, the 150mg dose of Pradaxa was superior to warfarin in terms of risk of stroke or blood clots when the population was assessed as a whole (relative risk [RR] 0.66; 95% confidence interval [CI] 0.53 to 0.82; p<0.001).
How did the researchers interpret the results?
The researchers said that 150mg Pradaxa taken twice daily may reduce the risk of stroke compared to warfarin, and this reduction applies across the different levels of atrial fibrillation associated with stroke risk. They also said that “stroke risk is similar regardless of the type of non-valvular atrial fibrillation” and that Pradaxa was “associated with lower rates of stroke than warfarin in patients with all three types of non-valvular atrial fibrillation”.
The press release from Boehringer Ingelheim also lists potential side effects of Pradaxa, which may include an increased risk of gastrointestinal side effects. It also states that in people over 75, Pradaxa may have a greater risk of a major bleed compared with warfarin.
The news coverage relates to a press release and the results that were presented at a cardiology conference detailing whether different subgroups of patients who received Pradaxa had a lower risk of stroke than those who were given warfarin.
This was a follow-up study of a clinical trial, published in 2009, which found that Pradaxa was better than warfarin in reducing the risk of strokes in people with atrial fibrillation. The study found that Pradaxa was associated with similar risk factors for stroke in people at greater and lower risk of stroke. It also found that the type of AF, whether temporary or persistant, had no impact on the effect of Pradaxa.
These news stories are based on a press release, which did not report the confidence intervals from the research. As such, it is not possible to say whether the overall difference between warfarin and Pradaxa in reducing risk of stroke reported in 2009 was maintained when each of the subgroups receiving Pradaxa were compared with warfarin.
The application for a European licence for Pradaxa for the prevention of stroke in people with atrial fibrillation has been submitted. An application to the FDA, the American equivalent to the European medicines regulatory body, has already been approved.