Warfarin and brain haemorrhage

“People who regularly take the blood-thinning drug warfarin may be increasing the risk of a fatal brain haemorrhage”, The Daily Telegraph reported. It said the drug is taken by many patients at risk from ischemic stroke to prevent blood clots from developing. However, a study has found that people who had a stroke and were taking the drug experienced twice as much bleeding. This in turn could cause a brain haemorrhage and death unless treated quickly.

This particular risk of warfarin has already been identified, and the aim of this study was to examine some of the details behind this risk. The benefits of warfarin are well known, but as with all drugs, there are some risks. This study itself did not measure up these benefits and risks (for example, how many ischaemic strokes the drug prevented), but instead looks at how warfarin might affect one aspect of brain haemorrhage. As the lead researcher is reported as saying, this study “shows the importance of good monitoring and adjustment of warfarin dose. People should talk to their doctors about the proper management of warfarin and learn the signs of stroke so they can get to an emergency room immediately if a stroke occurs”.

Where did the story come from?

Dr Matthew L. Flaherty and colleagues from the University of Cincinnati carried out this research. The study was funded in part by the National Institute of Neurological Disorder and Stroke and a University of Cincinnati College of Medicine Medical Student Summer Research Fellowship. The study was published in the peer-reviewed medical journal, Neurology.

What kind of scientific study was this?

Warfarin use has long been associated with a greater risk of death in people who have an intracerebral haemorrhage (ICH), but it is not known exactly how it has this effect. The authors of this retrospective cohort study had a theory that warfarin use might affect intracerebral haemorrhage size, and their study was designed to test this possibility.

The researchers used medical records to identify all adults who had been admitted to hospital with an ICH in the Greater Cincinnati region in 2005. Patients living outside the region were excluded, as were patients who had previously experienced an ICH, or where the cause of bleeding was trauma or was associated with brain tumours or encephalitis, surgical procedures (endarterectomy), or with the early hospital (thrombolytic) treatment of an ischaemic stroke. Data for 258 eligible patients was extracted from the records, including their age, sex, whether they were taking anti-clotting medications (including warfarin or aspirin), what other conditions they had (e.g. diabetes, heart disease, high blood pressure), and location of the ICH.

The researchers also looked at an indicator of how well a person’s blood clots, called the INR, which was measured when the patients first presented at hospital. The INR is a ratio and a high INR indicates a higher risk of bleeding (i.e. clots are slow to form), while a low INR, close to one, indicates a normal clotting profile in the blood. People taking warfarin to prevent ischaemic stroke from atrial fibrillation, for example, aim for a mid-range INR (two to three). Data on INR was missing for 22 patients, none of whom took warfarin. The researchers assigned these people an INR value of one. The researchers also measured the volume of each participant’s ICH on their first brain scan (MRI or CT scan) using a standard technique, and recorded the time taken between onset of the stroke and the scan.

Statistical methods were then used to look at whether taking warfarin and other factors affected the size of a person’s ICH. To begin with, each factor was analysed separately (univariate analysis). Then, a second analysis of the effect of individual factors found to be associated with ICH size in the univariate analysis was carried out, taking into account all of the other associated factors (multivariate analysis). Because warfarin use was strongly associated with INR value (higher warfarin use associated with higher INR values), only INR values were used in this second analysis. The researchers also looked at the relationship between these factors and death within 90 days of the stroke.

What were the results of the study?

The researchers identified 258 people (average age 68.5 years) who had been admitted with ICH in the study period. Of these, 51 had been taking warfarin. Warfarin users had higher average INR values than non-users (3.1 compared with 1.1, p<0.001). When looking at individual factors, researchers found that warfarin use, location of the haemorrhage in the brain lobes, age, and shorter time between the stroke and the brain scan were associated with larger ICHs. There was a trend for patients with higher INRs to have larger ICHs, although this trend did not reach significance.

The researchers included INR values rather than warfarin use in their second (multivariate) analysis, as there was a strong link between these two factors. This second analysis found that those with a high INR (three or above) were more likely to have larger ICHs than those with a low INR (less than 1.2). ICH size was not significantly different between patients with mid-range INRs (1.2-3) and those with low INRs. Haemorrhages were larger in people who had a shorter time between onset of their stroke and the brain scan, and haemorrhages in the lobes of the brain were larger than those deep in the brain.

A higher INR (three or above) was also found to be associated with about twice the risk of death within 90 days compared to those with low INR (less than 1.2).

What interpretations did the researchers draw from these results?

The researchers concluded, “Warfarin use was associated with larger initial intracerebral hemorrhage (ICH) volume” for INRs above three, and that this difference “likely accounts for part of the excess mortality in this group”.

What does the NHS Knowledge Service make of this study?

As the study authors report, it is already known that warfarin use can increase risk of death in people who have a haemorrhagic stroke. This aim of this study was to take a closer look at the reasons behind this. There are a number of points to note when interpreting this study:

• The number of people taking warfarin was relatively small. Results will need to be replicated in a larger, preferably prospective, study to confirm these findings.
• There is the possibility that, other than the drug itself, there were underlying differences between people on warfarin and those not on warfarin which affected the results. This is a limitation of all studies of this type. Although the researchers took into account some factors in their analyses, there may have been other factors that had an effect but were not assessed.
• Some people (85) in this study were taking drugs other than warfarin, such as aspirin, that can affect clotting. The main analyses in this study looked at the effect of INR on ICH size, and did not adjust for use of other medications. It is possible that the sizes of the ICHs in this study partially reflect not only the effects of warfarin alone, but the effects of these other drugs, or other internal or external factors, such as diet, which are known to affect INR.
• On admission for ICH, people may have received treatment to reverse the effects of any anti-clotting medication they were taking. The authors reported that it was unclear from their medical records whether the INR measurements were taken before or after this treatment, and that this could have affected their results.
• As this study only looked at people who had experienced an ICH, it cannot show what proportion of people who take warfarin experience an ICH compared to those who do not take warfarin. Therefore, it is not possible to determine from this study whether the risk of ICH or risk of death after ICH is increased with warfarin, or whether warfarin prevented death from other causes.

The benefits of anti-clotting drugs are well known, but as with all drugs, there are some risks to taking warfarin. These risks can be minimised by taking prescribed doses of warfarin according to doctors’ directions, and attending any scheduled check-ups so that effects of warfarin can be monitored.