Intrinsic Coagulation Pathway, History of Headache, and Risk of Ischemic Stroke: a story about interacting risk factors

Yup, another paper from the long-standing collaboration with Leiden. this time, it was PhD candidate HvO who came up with the idea to take a look at the risk of stroke in relation to two risk factors that independently increase the risk. So what then is the new part of this paper? It is about the interaction between the two.

Migraine is a known risk factor for ischemic for stroke in young women. Previous work also indicated that increased levels of the intrinsic coagulation proteins are associated with an increase in ischemic stroke risk. Both roughly double the risk. so what does the combination do?

Let us take a look at the results of analyses in the RATIO study. High levels if antigen levels of coagulation factor FXI are associated with a relative risk of 1.7. A history of severe headache doubles the risk of ischemic stroke. so what can we then expect is both risks just added up? Well, we need to take the standard risk that everybody has into account, which is RR of 1. Then we add the added risk in terms of RR based on the two risk factors. For FXI this is (1.7-1=) 0.7. For headache that is 2.0-1=) 1.0. So we would expect a RR of (1+0.7+1.0=) 2.7. However, we found that the women who had both risk factors had a 5-fold increase in risk, more than what can b expected.

For those who are keeping track, I am of course talking about additive interaction or sometimes referred to biological interaction. this concept is quite different from statistical interaction which – for me – is a useless thing to look at when your underlying research is of a causal nature.

What does this mean? you could interpret this that some women only develop the disease because they are exposed to both risk factors. IN some way, that combination becomes a third ‘risk entity’ that increases the risk in the population. How that works on a biochemical level cannot be answered with this epidemiological study, but some hints from the literature do exist as we discuss in our paper

Of course, some notes have to be taken into account. In addition to the standard limitations of case-control studies, two things stand out: because we study the combination of two risk factors, the precision of our study is relatively low. But then again, what other study is going to answer this question? The absolute risk of ischemic stroke is too low in the general population to perform prospective studies, even when enriched with loads of migraineurs. Another thing that is suboptimal is that the questionnaires used do not allow to conclude that the women who report severe headache actually have a migraine. Our assumption is that many -if not most- do. even though mixing ‘normal’ headaches with migraines in one group would only lead to an underestimation of the true effect of migraine on stroke risk, but still, we have to be careful and therefore stick to the term ‘headache’.

HvO took the lead in this project, which included two short visits to Berlin supported by our Virchow scholarship. The paper has been published in Stroke and can be seen ahead of print on their website.

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Diane 35 and thrombosis risk – Zembla broadcast

The oral contraceptive pill ‘Diane 35- was’ in the news again. I wrote about the diane-35 pill on this website before, even twice,  when there was a broadcast of the radio show Argos.

The first time I wrote:

[…] this is a bit strange: there is nothing new about the information that third and fourth generation oral contraceptives have an increased risk of thrombosis compared to the risk conveyed by second generation oral contraceptives. Because the desired effects of the older and newer generation pills are similar (not getting pregnant, preventing or curing acne) there is limited, if any, reason to prescribe the newest and more expensive pills. See also the recent comment by Helmerhorst and Rosendaal in the BMJ. However, still 160.000+ (Diane 35) 500.000 (third generation) women take these newer pills. […]

Those words also fit the broadcast of the TV show Zembla last week. Zembla has a reputation to be ‘activist reporters’ and some of the broadcast is not to my taste. It is however good to see that Zembla tried to figure out how it is possible that Diane-35, which is not registered as an anti-conception pill, still gets prescribed as such. However, the broadcast leaves me unsatisfied for it does not provide answers, or even get to talk to everybody they wanted to? (Why did they reporters did not proceed to work on their WOB? a missed change!)

As in the previous two blog posts on this topic, I feel like these story are important but they also need to have the proper amount of nuance. Therefore, also this time I conclude with saying that the absolute risk of thrombosis in young women (both venous and arterial) is very low, even when using oral contraceptives. But all unnecessary risk without any benefit that can be avoided should be avoided. As always, consult your GP if you have any questions.

Grant awarded to investigate the long term effects of cardiovascular disease at a young age

Today I got a letter from the Leiden University Fund (LUF) to inform me that the grant we requested was granted. This is great, because now we can investigate the long-term effects of young stroke, myocardial infarction and peripheral arterial disease. We will do this by linking our data from the RATIO to the several national databases (e.g. cause of death registries and hospital admissions) that are under control by the central bureau of statistics (CBS). I will perform this research together with AM and other Italian colleagues from Milan. 

The grant (11K) that was awarded is the Den Dulk Moermans Fonds, which exist since 2010, as we can read from the Dutch information the LUF website:

Het Den Dulk-Moermans Fonds is opgericht in 2010 na ontvangst van een erfenis van dhr. A.M. den Dulk. De doelstelling van het Fonds is het financieren van onderzoek naar gezondheid in de breedste zin van het woord.

Grant awarded to investigate the role of coagulation FVIII in the aetiology of ischaemic stroke in RATIO study

I just received a letter from the KNAW stating that the grant proposal I sent to one of the fund of the KNAW, the van Leersumfunds, was awarded. From their website, we can only learn a little about this fund:

“The Van Leersum Fund supports neuro(bio)logical, radiological and pharmaceutical research by awarding a series of research grants.

The Fund was established in 1922 and is named after P. van Leersum. The assets of the fund are made up of his estate and the estate of Ms I.G. Harbers-Kramer.”

With this grant we will be able to measure coagulation favtor VIII in the ischaemic stroke substudy of the RATIO study. Coagulation factor FVIII is one of the most potent risk factors for venous thrombosis in the coagulation system, and were quite curious what effect it has on the risk of ischaemic stroke in young women.

Diane 35 and thrombosis risk – Argos broadcast part II

Last week I wrote a post after hearing the radio broadcast of Argos. They concluded that broadcast with the promise to discuss how it is possibe that a more expensive, just as effective medicine which has more side effects still can be prescribed (in large numbers) in the Netherlands.

So I’ve listen with great interest the second part of the story, which can be heard on the Argos website. They journalists did a good job by covering all sides of the story , and they provide insight in the differences between ‘advertisement’ and ‘providing information’. What if information that is provided is only one sided? Does that count as advertisement? and if you want to play a nice game during the broadcast, ‘spot the logical fallacy’ is good suggestion… Gems!

In case you are wondering: the absolute risk of thrombosis in young women is low, even when using oral contraceptives. But I still believe that all unnecessary added risk without any benefit that can be avoided should be avoided by you in dialogue with your GP!

Diane 35 and thrombosis risk – Argos broadcast

The oral contraceptive pill – especially the Diane 35- was in the news again. However, this is a bit strange: there is nothing new about the information that third and fourth generation oral contraceptives have an increased risk of thrombosis compared to the risk conveyed by second generation oral contraceptives. Because the desired effects of the older and newer generation pills are similar (not getting pregnant, preventing or curing acne) there is limited, if any, reason to prescribe the newest and more expensive pills. See also the recent comment by Helmerhorst and Rosendaal in the BMJ. However, still 160.000+ (Diane 35) 500.000 (third generation) women take these newer pills. Since thrombosis risk might be highest in the first few months, it is unclear whether these women all should switch to the safer second generation oral contraceptives. But for women who get their first prescription, a second generation oral contraceptive the best way to go (also according the Dutch GP guidelines).

A lot of the research on this topic has been executed by my colleagues from both the MEGA study and the RATIO study. Want to learn more about the pill controversy, please listen this episode of Argos, a Dutch radio programme.

In case you are wondering: the absolute risk of thrombosis in young women is low, even when using a newer generation oral contraceptives. But all added risk that can be avoided should be avoided by you in dialogue with your GP!

Paper selected as most important paper

The editors of Circulation: Cardiovascular Interventions perform perform a periodic  ‘Topic Review’  which (and I quote)

summarizes the most important manuscripts, as selected by the editors that have published in the Circulation portfolio. The studies included in this article represent the most noteworthy research in the area of peripheral arterial disease. (Circ Cardiovasc Interv. 2012;5:e39-e44.)

Our research on the effect of activation of the intrinsic coagulation proteins and their effects on ischaemic stroke risk -and not on myocardial infarction risk- was selected as one of the most important manuscripts int he field of peripheral arterial disease. This study was performed in collaboration with the Maastricht University Medical Center. The summary by these editors can be read below.

Continue reading “Paper selected as most important paper”