Migraine and cardiovascular disease: systematic review and meta-analysis
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b3914 (Published 27 October 2009) Cite this as: BMJ 2009;339:b3914
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One explanation for the finding of Schurks et al (1) of an increase
of risk of ischaemic stroke with migraine with aura, especially in women
taking oral contraceptives, could be the link between migraine with aura
and patent foramen ovale (2). This combination would predispose to
paradoxical cerebral embolism much more than patent foramen ovale alone.
This mechanism would also explain why there seems to be little relation
with other cardiovascular disease.
References:
1. Markus Schürks, Pamela M Rist, Marcelo E Bigal, Julie E Buring, Richard
B Lipton, and Tobias Kurth.
Migraine and cardiovascular disease: systematic review and meta-
analysis. BMJ 2009; 339: b3914
2.S J Tapper, F D Sheftell and M E Bigal.
The patent foramen ovale - migraine question.
Neurol. Sci. 2007; 27: S118-S123
Competing interests:
None declared
Competing interests: No competing interests
I have read with interest your systematic literature review on
migraine and ischaemic stroke published in this weeks edition (1) and was
surprised to see that our paper 'Ischamic stroke in young women: a nested
case-control study using the UK General Practice Research Database'(GPRD)
(2) was excluded from the review. The reason given for the exclusion of
our paper, which had been previously included in a systematic review on
the same subject in 2005 (3), was that it was a "case-control study from a
database that also contained a cohort analysis". This statement does not
provide an adequate reason for exclusion from the study where the
inclusion criteria specified that studies must have been either case-
control or cohort studies.
The inclusion criteria for your systematic review were:
(a) That the study was of case-control or cohort design
(b) That the authors must investigate migraine or probable migraine
(c) That the authors must clearly define the criteria for the
cardiovascular event
(d) That the authors must use a multivariable model or matching procedure
that controls for confounding
(e) That the authors must provide relative risk estimates
Reading through our paper on ischaemic stroke in young women I can
only conclude that our paper does, in fact, fulfill all of the above
criteria.
(a) The study was a nested case-control study of ischaemic stroke in
women aged 15 to 49 years with at least 6 months data contribution to the
GPRD between 1992 and 1998. There were 190 cases of ischaemic stroke and
1129 controls.
(b) We investigated migraine as a risk factor for stroke and defined our
criteria for the presence of migraine clearly in the paper. There were 16
cases and 44 controls with a history of migraine.
(c) Ischaemic stroke was, again, clearly defined in the case definition of
the paper as: "women with a first diagnosis of cerebrovascular accident,
cerebral thrombosis, cerebellar infarction or cerebellar thrombosis.." All
cases and supporting evidence of diagnosis in their medical record as is
common practice for case identification when using the GPRD
(d) Cases and
controls were matched by age and general practice; multivariable
conditional logistic regression models were used to control for other
confounders
(e) Adjusted Odds Ratios with 95% confidence intervals were presented. The
adjusted OR for migraine was 2.33 (95% confidence interval 1.04, 5.21).
The cohort study was used to estimate the incidence of ischaemic
stroke in young women, which was 3.56/100,000/year for the study
population. Ischaemic stroke is a rare event which meant that the case-
control study nested within the study population selected from the GPRD,
was the most appropriate study design for the investigation of factors
associated with an increased risk of stroke.
The methodology for conducting systematic reviews has been developed
to minimise the risk of selection bias. One of the ways in which this is
achieved is to set out clear inclusion and exclusion criteria for papers.
Excluding studies that clearly fulfil the inclusion criteria for a review
is a methodological weakness and one that calls into question the
robustness of the review as a whole. Moreoever, as part of systematic
review methodology it is usual to contact authors for further information
where doubts have arisen, yet no such communication was made in this case.
Alison Nightingale PhD
1. Shurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth TK.
Migraine and cardiovascular disease: systematic review and meta-analysis.
BMJ 2009; 339:3914b doi:10.1136/bmj.b3914
2. Nightingale AL, Farmer RDT. Ishchaemic stroke in young women. A
nested case-control study using the UK General Practice Research Database.
Stroke 2004; 35:1574-1578
3. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic
stroke in people with migraine: systematic review and meta-analysis of
observational studies. BMJ. 2005; 336:63 doi:10.1136/bmj.38302.504063.8F
Competing interests:
None declared
Competing interests: No competing interests
Authors' Response
Reply to Alison L. Nightingale: Exclusion of papers from systematic
reviews should be better justified
Thank you for giving us the opportunity to re-emphasize our inclusion
and exclusion criteria of studies into our meta-analysis on the
association between migraine and risk of cardiovascular events [1] and to
clarify why we did not include your study [2].
You have correctly stated the first five of our a priori defined inclusion
criteria. However, we had a sixth criterion, which specified the handling
of competing studies utilizing the same data base. Specifically we stated:
“If multiple studies were published from the same study population we only
included data from the report with the longest follow-up, or if similar
with the larger number of participants, if all studies had a cohort
design, or we included data from the cohort study instead of the case-
control study, if different designs were used and we included subgroup
analyses of competing studies, if these data were only provided in one of
the studies.” Both your and another study [3] used data from the UK
General Practice Research Database (GPRD) with largely overlapping time
periods. Since the other study [3] used a cohort design to evaluate the
association between migraine and ischemic stroke, we—based on our
criteria—included this study into our meta-analysis. Inclusion of both
studies would have resulted in double-weighting the risk of the
association between migraine and ischemic stroke from the same underlying
study population. As expected, the association between migraine and
ischemic stroke was very similar in your [2] (RR=2.33; 95% CI, 1.04-5.21)
and in the cohort study [3] (RR=2.49; 95% CI, 1.62-3.83). There was a
third study [4] that used the GPRD and we only included this study for the
subgroup analysis of the association between migraine and transient
ischemic attacks since it was the only one that provided information about
this particular outcome. We did proceed similarly with other studies,
including our own work [5] as indicated in our manuscript [1].
Reply to Edmund J. Dunstan: Migraine with aura and stroke
The precise biological mechanisms why patients with migraine with
aura have an increased risk of ischemic stroke are currently unclear, but
likely multifactorial and complex. During the past years, a potential link
between patent foramen ovale (PFO), migraine with aura, and risk of
ischemic stroke has been discussed intensively [6]. Paradoxical micro-
embolization through a PFO has been hypothesized as a potential mechanism
increasing the risk of ischemic stroke in migraine with aura. However,
there is little published evidence that presence or absence of a PFO
modifies the association between migraine with aura and ischemic stroke.
To our knowledge, there is only one study that has investigated whether
the association of migraine with aura and ischemic stroke differs by
having a PFO or not and the authors did not find a difference [7]. In
addition, the grade of evidence of the association between migraine and
PFO has recently been judged as only low to moderate [8]. Further, a
population-based study did not find an association between migraine and
PFO [9]. Hence, at present the notion that a PFO is responsible for the
increased risk of ischemic stroke among patients with migraine with aura
remains a hypothesis unsubstantiated by firm data.
Markus Schürks, MD, MSc
Tobias Kurth, MD, ScD
1. Schürks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T.
Migraine and cardiovascular disease: a systematic review and meta-
analysis. BMJ 2009;339:b3914.
2. Nightingale AL, Farmer RD. Ischemic stroke in young women: a
nested case-control study using the UK General Practice Research Database.
Stroke 2004;35(7):1574-8.
3. Hall GC, Brown MM, Mo J, MacRae KD. Triptans in migraine: the
risks of stroke, cardiovascular disease, and death in practice. Neurology
2004;62(4):563-8.
4. Becker C, Brobert GP, Almqvist PM, Johansson S, Jick SS, Meier CR.
Migraine and the risk of stroke, TIA, or death in the UK (CME). Headache
2007;47(10):1374-84.
5. Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al.
Migraine, headache, and the risk of stroke in women: a prospective study.
Neurology 2005;64(6):1020-6.
6. Diener HC, Kurth T, Dodick D. Patent foramen ovale, stroke, and
cardiovascular disease in migraine. Curr Opin Neurol 2007;20(3):310-9.
7. MacClellan LR, Giles W, Cole J, Wozniak M, Stern B, Mitchell BD,
et al. Probable migraine with visual aura and risk of ischemic stroke: the
stroke prevention in young women study. Stroke 2007;38(9):2438-45.
8. Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale and
migraine: a quantitative systematic review. Cephalalgia 2008;28(5):531-40.
9. Rundek T, Elkind MS, Di Tullio MR, Carrera E, Jin Z, Sacco RL, et
al. Patent foramen ovale and migraine: a cross-sectional study from the
Northern Manhattan Study (NOMAS). Circulation 2008;118(14):1419-24.
Competing interests:
None declared
Competing interests: No competing interests