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Oral contraceptives and myocardial infarction: results
of the MICA case-control studyCommentary: Oral contraceptives and myocardial
infarction: reassuring new findings
Oral contraceptives and myocardial infarction: results
of the MICA case-control study
Nicholas Dunn a Drug Safety Research Unit, Bursledon Hall,
Southampton SO31 1AA, b London
School of Hygiene and Tropical Medicine, London WC1 6FH, c Department of Organisational Psychology,
Manchester School of Management, UMIST, PO Box 88, Manchester
M60 1QD, d Department of Public Health, Greater Glasgow Health Board,
Dalian House, PO Box 15327, Glasgow G3 8YU, e Medicines Monitoring Unit, Department of Clinical
Pharmacology and Therapeutics, Ninewells Hospital Medical School,
Dundee DD1 9SY, f Department of Surgery,
South Manchester University Hospital, West Didsbury, Manchester
M20 8LR, g Wolfson Unit of Clinical Pharmacology, University of
Newcastle, Newcastle upon Tyne NE2 4HH
Correspondence to: Dr Dunn
ndunn{at}dsru.u-net.com
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Abstract |
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Introduction
Methods
Results
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Objectives:
To determine the association between
myocardial infarction and use of different types of oral contraception
in young women.
Design:
Community based case-control study. Data from interviews and general practice records.
Setting:
England, Scotland, and Wales.
Participants:
Cases (n=448) were recruited from women
aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without
a diagnosis of myocardial infarction matched for age and general practice.
Main outcome measures:
Odds ratios for myocardial
infarction in current users of all combined oral contraceptives
stratified by their progestagen content compared with non-users;
current users of third generation versus second generation oral contraceptives.
Results:
The adjusted odds ratio for myocardial
infarction was 1.40 (95% confidence interval 0.78 to 2.52) for all
combined oral contraceptive users, 1.10 (0.52 to 2.30) for second
generation users, and 1.96 (0.87 to 4.39) for third generation users.
Subgroup analysis by progestagen content did not show any significant
difference from 1, and there was no effect of duration of use. The
adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an
oral contraceptive, and 88% had clinical cardiovascular risk factors
or were smokers, or both. Smoking was strongly associated with
myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for
smoking 20 or more cigarettes a day.
Conclusions:
There was no significant association
between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have
wide confidence intervals. There was no significant difference between
second and third generation products.
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Key message
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Introduction |
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Introduction
Methods
Results
Discussion
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Recent studies on the association between use of oral
contraceptives and myocardial infarction have suggested that any risk is confined to women with known cardiovascular risk
factors.1-3 Reported odds ratios vary between 1.67 and
5.01 for comparison of current users of all types of combined oral
contraceptive versus non-users. Only one study, however, had sufficient
power to report on the variation in risk between different types of
oral contraceptive.3 This study found an odds ratio of
0.28 (95% confidence interval 0.09 to 0.86) for current users of
third generation versus second generation oral contraceptives. Third
generation oral contraceptives were defined as those containing the
progestagens gestodene and desogestrel combined with ethinyloestradiol
and second generation as containing the progestagens levonorgestrel and
norethisterone combined with less than 50 µg of
ethinyloestradiol. The MICA study was designed to investigate
whether the risk of myocardial infarction was influenced by oral
contraceptive use overall and to study in more detail the effect of
different types of oral contraceptives among women in England,
Scotland, and Wales.
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Methods |
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The research protocol for this study has been published elsewhere.4 This was a community based, retrospective case-control study undertaken in the population of England, Scotland, and Wales.
Cases
Women were eligible as cases if they were aged 16-44 and had suffered an incident myocardial infarction between 1 October
1993 and 16 October 1995. Exclusion criteria were a history of
myocardial infarction, pregnancy in the 6 weeks before the date of the
myocardial infarction, or a history of menopause, hysterectomy,
oophorectomy, and breast or ovarian cancer. Cases were identified from
hospital inpatient episode statistics and the deaths register of the
Office for National Statistics for all England and Wales and from the
Information and Statistics division of the Department of Health or the
registrar general's office in Scotland. International classification
of diseases, 9th revision (ICD-9) code 410 or 10th revision (ICD-10)
code 121 were used as identifiers of acute myocardial infarction. A
validation study in Tayside, Scotland, showed 67% sensitivity and
100% specificity in using only these codes for identifying the
cases.5 Diagnostic information for each potential case was
extracted from the hospital notes, and these data were submitted to a
panel of three cardiologists, blinded to exposure status, for
confirmation of diagnosis. Criteria for diagnosis were according to the
World Health Organisation, with inclusion of the case depending on a
majority decision of the diagnosis as being "definite" or
"possible."6 Cases in which the woman died before
reaching hospital or before investigations had been done were validated
on the result of the necropsy findings. Those without necropsy were
excluded. Women were interviewed in the community by using a structured
questionnaire, after consent was obtained from the general practitioner
and the patient. For women who died we interviewed a proxy (husband or
a close relative).
Controls
Control women were selected from the general practice with which the index woman was registered at the time of her
myocardial infarction. They were closely matched by age: each general
practitioner provided a list of women with date of birth closest to the
index woman's (six older and six younger), and we interviewed the four
controls with closest date of birth (two older and two younger) from
among those who consented.
Interview data
The interview included questions on medical history of cardiovascular risk factors, obstetric history (including history of high blood pressure), use of contraception in the 5 years
before the myocardial infarction (recorded in a calendar), drug
history, family history of premature cardiovascular disease, and
socioeconomic status (by employment history of interviewee and
partner). Current use of oral contraceptives was defined as use within
3 months of the date of myocardial infarction to enable direct
comparisons with results from WHO and transnational
studies.
1 3
Interviews were carried out between December
1996 and February 1998 and thus the length of recall varied between 14 months and 51 months.
Risk factors
Risk factors and exposure data (oral
contraceptive use, blood pressure, smoking, lipid concentrations, and
family history) were validated by checking against the interviewee's general practitioner record or occasionally against records from family
planning clinics. We calculated odds ratios using three different
measures of exposure: interview data, general practitioner record data,
and a compromise with exposure data taken from general practitioner
records when the two sources disagreed on the type of oral
contraceptive and interview data when there was disagreement on
whether or not there was any current exposure to oral contraception.
Control of observer bias
All research assistants were
trained in a standardised technique and were issued with a standard
field manual. They were quality controlled throughout the study by
means of accompanied and taped interviews.
Statistical power
With data from 448 cases and 1728 controls available for statistical evaluation and a prevalence of
exposure to third generation oral contraceptives of 3.7% in the
controls the power of this study to detect an odds ratio of 2 for third generation users versus no use was 81% at the 5% significance level.
The power for second generation oral contraceptive users (exposure
7.2%) versus no use was 96%.
Statistical analysis
We fitted conditional logistic
regression models with STATA (StataCorp, Texas, release 5, 1997) with
outcome (case-control status) as the dependent variable. Unadjusted
univariate odds ratios were estimated for category of contraceptive use
and for all potential confounding variables. In a first, planned, multivariate analysis a stepwise backward elimination procedure was
carried out to identify those potential confounding variables which
were independently related to outcome by using an arbitrary significance level for expulsion from the model of P<0.05. The odds
ratios for category of contraceptive use were then adjusted for those
confounding factors which entered the stepwise regression model. These
are referred to as "select." In a second multivariate analysis we
adjusted the odds ratios for contraceptive use category for all
potential confounding factors. These are referred to as "full."
Both analyses are presented. Finally, unconditional logistic regression
models were fitted to selected subgroups of cases and controls, again
with STATA.
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Incidence rate
On the basis of 1224 cases identified from source data (see
figure), the incidence rate of myocardial infarction was 0.5 per 1000 women years.
Cases and controls
We interviewed 413 women who had experienced myocardial infarction
(index women) and 35 surrogates in cases when the index woman had died,
representing 60.4% of the total eligible cases. There was a large
difference in the interview rate between surviving index women and
surrogates (figure). A total of 1728 control women were interviewed,
giving a mean of 3.86 controls per case. Age matching between cases and
controls was good, the median age difference being only 18 days (table 1). We validated the data from 436 (97%) cases and 1716 (99%) controls with general practitioner or family planning
records.
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Risk factors
Table 1 shows the distribution of the potential confounders
between the cases and controls. Most of these covariates were shown to
be associated with an increased risk of myocardial infarction: smoking,
diabetes mellitus, and history of angina having the largest effects. In
88% of cases (versus 36% of controls) we found one or more
cardiovascular risk factors. In particular, 80% (360) of the index
women were smokers compared with 30% (520) of controls, and there was
a clear gradient of risk with increasing number of cigarettes smoked
per day. The population attributable fraction for smoking in the year
before the myocardial infarction was 73%. Consumption of alcohol,
taking regular exercise to keep fit, and being in paid work in the past
year were all associated with a decreased risk of myocardial infarction.
Exposure to oral contraceptives
Table 2 shows the data on exposure to oral contraceptives in the 3 months before the date of the myocardial infarction. From the subject
interviews, 87% of index women were not taking an oral contraceptive
in this time period.
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Univariate analysis
Although most of the point estimates of the unadjusted odds
ratios were below 1, the 95% confidence intervals predominantly
include 1 (table 2). We further subdivided the third generation oral
contraceptives that contain desogestrel into two classes: those with
low dose (20 µg) and those with standard dose (30 µg)
ethinyloestradiol. The odds ratio for low dose was 0.46 (95%
confidence interval 0.13 to 1.55) and that for standard dose was 1.57 (0.59 to 4.17), but these were based on only three and six cases, respectively.
Multivariate analysis
Table 3 shows the odds ratios from the "select" model
adjusted for number of cigarettes smoked a day, diabetes mellitus,
family history of ischaemic heart disease, other drugs taken in past
year, body mass index, history of hypertension, history of angina, and
whether or not blood pressure was taken in past year. Adjustment tended
to increase the odds ratios, but none was significant. There was no
effect of duration of use of oral contraceptives. There were some
differences in the point estimates of odds ratios derived from the two
data sources (interview and general practitioner record data), but the
95% confidence intervals overlapped.
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that is,
adjusted for all the factors in the "select" model, plus all
additional variables examined in the univariate analysis (table 1). The
odds ratios are all higher than for the select model but with wider
confidence intervals. Adjusted odds ratios for third generation versus
second generation users were as follows: from patient interview data
2.06 (0.77 to 5.50), from general practitioner record data 1.41 (0.54 to 3.70), and from interview and general practitioner data combined
1.78 (0.66 to 4.83).
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Discussion |
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Myocardial infarction is rare in this age group of women. The point estimates suggest that the risk of myocardial infarction is increased slightly by the use of oral contraceptives, although adjustment for a large number of confounders introduced some uncertainty in the risk estimates, as shown by wide 95% confidence intervals. The point estimates were greater for third than for second generation oral contraceptives, but the differences observed were not significant.
Smoking was an important risk factor (the population attributable fraction being 73%), and other cardiovascular risk factors were also important. In line with the results from the WHO study1 and the transnational study,3 among those who were current users of oral contraceptives the absence of a blood pressure check in the year preceding the index woman's myocardial infarction showed a positive association with myocardial infarction, although this was not significant (odds ratio 2.07; 0.81 to 5.30). The positive association between multiparity and myocardial infarction has been reported before7 as has that with pre-eclampsia.1 The beneficial effect of consumption of alcohol is in keeping with results of other studies,8 as is the benefit of exercise and being in employment in the past year.9
Potential bias
Possible weaknesses of this study were low interview rates,
misclassification of exposure, and selection bias. We interviewed 73%
of the women who survived myocardial infarction but achieved proxy
interviews for only 20% of those who died, which may have introduced a
bias if, for example, certain types of oral contraceptive were
particularly liable to cause sudden death from myocardial infarction.
This does not seem likely as oral contraceptives were not found to be a
significant risk factor in this study, but it cannot be entirely
discounted. Recall bias may have occurred because we asked interviewees
to recall contraceptive habits. The adverse publicity about third
generation oral contraceptives generated by the "Dear Doctor"
letter from the United Kingdom Committee on Safety of Medicines in
October 1995 may have biased responses to our questions, although,
whenever possible, interviewees were blinded to the main objective of
the study. Also, we provided photographs of all marketed oral
contraceptives to increase the accuracy of recall. Furthermore, we
validated the exposure data from written records, and the 
score for
agreement in exposure data between the two sources was 0.8 for both
cases and controls. As shown in tables 2 and 3 there were some
differences in odds ratios with the two different sources, but overall
the measures of effect were similar, and the "compromise" odds
ratios represent our best estimate of the true effect. Some effect of selection bias is possible because controls were women who responded to
a request to participate, and such women may not be representative of
the population, but on average it was necessary to approach only 6.6 (range 4-26) of the closest age matched controls.
Relevance of results
The importance of the MICA study is that it had sufficient
power to examine the effects of oral contraceptives with differing
progestagen content on the incidence of myocardial infarction with very
close age matching between cases and controls. Our results do not agree
with those of the European transnational study,3 although
the United Kingdom results from that study and the present study show
considerable overlap and are compatible within the bounds of random
error. Other studies have been hampered by small numbers of
participants exposed to oral contraceptives but generally their results
also suggest that there is no difference in risk of myocardial
infarction between different preparations.
1 2 10
Although the WHO study reported an adjusted odds ratio of 5.01 (2.54 to
9.90) for European oral contraceptive users overall compared with
non-users,1 and this contrasts with an odds ratio of 1.40 in this study, the populations studied were quite different. The WHO
study recruited 55% of their cases from Eastern Europe, where there
may be inadequate screening for risk factors among oral contraceptive
users, and it is pertinent that the odds ratio for the subset of United
Kingdom users was 2.10 (0.63 to 7.07), which is similar to our results.
Comparison of the MICA study with similar studies carried out in the
1980s, which found odds ratios for current use of oral contraceptives
varying between 1.2 and 3.5,
11 12
is difficult because of
changes in the formulations of the pills and because of probable
improvements in routine medical care. The fact that most women with
myocardial infarction in the present study were not taking any oral
contraception suggests that doctors were cautious in their prescribing
habits for older women who might be at risk. Our results for smoking
and other cardiovascular risk factors agree with those of all the
recent studies on this topic. These factors are of overriding
importance in the aetiology of myocardial infarction in this age group
and in comparison the use of oral contraception makes little or no difference.
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Acknowledgments |
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We thank all the women and next of kin who agreed to be interviewed, hospital records staff, general practitioners and surgery staff, and those who worked on the MICA project as follows: National Centre staff: Ann Arscott (national project manager), Jan Phillips (administrator), Susan Jay (quality control officer), Greg Gallagher and Caroline Keal (data entry clerks), Annette Kinsella (data programmer), Gretl McHugh (epidemiological support), Gill Mein and Deborah Curle (study advisors); Southampton Centre staff: Penny Nettelfield, Julie Pring, Rachael Green, Lesley Foulkest, Julie Richardson, Shona Burman-Roy, Jo Lockett, Liz Bale, and Yvonne Egan-Davidson (research assistants), Dr Derek Waller (local diagnostic committee); Manchester Centre staff: Mr Harvey Chant (medical coordinator), Jane Richardson (project manager), Jill Carley, Linda Robinson, Helen Shea, Tamsin Warner, Joanne Watson, and Heather Youngson (research assistants), Jane Booth (secretary), Dr Nicholas Brooks (local diagnostic committee); Glasgow Centre staff: Hilary Davison (project manager), Edith Hamilton, Sheena Mitchell, Susan Brogan, and Margaret Carlin (research assistants), Anne Currie (secretary), Professor Ross Lorimer (local diagnostic committee). Newcastle Centre staff: Judy Bland and Lyn Cassidy (research assistants), Dr Gary Ford (local diagnostic committee); National Diagnostic Committee: Dr Richard Jones, Professor David de Bono; Scientific Review Board: Miss Angela Mills, Professor Martin Vessey, Professor Michael Langman, Dr Kenneth MacRae, Professor David de Bono.
Contributors: ND and RM (principal investigator) initiated the study and wrote the protocol with MT, LdeC, CMcC, TMMacD, and ST. MT was principal scientific advisor. BF carried out the statistical analysis. All the authors contributed to the revision of the paper, which was originally drafted by ND. All the authors sat on the steering committee throughout the study. RM is the guarantor for the study.
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Footnotes |
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Funding: Unconditional grant from NV Organon and Schering AG.
Competing interests: None declared.
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References |
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Abstract
Introduction
Methods
Results
Discussion
References
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| 1. | WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international case-control study. Lancet 1997; 349: 1202-1209[Medline]. |
| 2. | Sydney S, Pettiti DB, Quesenbery CP, Klatsky AL, Ziel HK, Wolf S. Myocardial infarction in users of low dose oral contraceptives. Obstet Gynecol 1996; 88: 939-944[Medline]. |
| 3. | Lewis MA, Heinemann LAJ, Spitzer WO, MacRae KD, Bruppacher R, on behalf of Trans-National Research Group on Oral Contraceptives and the Health of Young Women. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Contraception 1997; 56: 129-140[Medline]. |
| 4. | Dunn NR, Thorogood M, de Caestecker L, Mann RD. Myocardial infarction and oral contraceptives, a retrospective case-control study in England and Scotland (MICA study). Pharmacoepidemiol Drug Safety 1997; 6: 283-289. |
| 5. | McAlpine R, Pringle S, Pringle T, Lorimer R, MacDonald T. A study to determine the sensitivity and specificity of hospital discharge diagnosis data used in the MICA study. Pharmacoepid Drug Safety 1998; 7: 311-318. |
| 6. | WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. A multinational case-control study of cardiovascular disease and steroid hormone contraceptives. J Clin Epidemiol 1995; 48: 1513-1547[Medline]. |
| 7. | Oliver MF. What is the difference between men and women? In: Oliver MF, Vedin A, Wilhelmsson C, eds. Myocardial infarction in women. Edinburgh: Churchill Livingstone, 1986:215-221. |
| 8. |
Tunstall-Pedoe H, Woodward M, Tavendale R, A'Brook R, McCluskey MK.
Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish heart health study: cohort study.
BMJ
1997;
315:
722-729 |
| 9. |
Rich-Edwards JW, Manson JE, Hennekens CH, Buring JE.
The primary prevention of coronary heart disease in women.
N Engl J Med
1995;
332:
1758-1766 |
| 10. | Jick H, Jick SS, Myers MW. Risk of acute myocardial infarction and low dose combined oral contraceptives. Lancet 1996; 347: 627-628[Medline]. |
| 11. |
Rosenberg L, Palmer JR, Lesko SM, Shapiro S.
Oral contraceptive use and the risk of myocardial infarction.
Am J Epidemiol
1990;
131:
1009-1016 |
| 12. |
La Vecchia C, Fransceschi S, De Carli A, Pampallona S, Tognoni G.
Risk factors for myocardial infarction in young women.
Am J Epidemiol
1987;
125:
832-843 |
(Accepted 25 February 1999)
Commentary: Oral contraceptives and myocardial
infarction: reassuring new findings
Øjvind Lidegaard Department of
Obstetrics and Gynaecology, Herlev Hospital, University of Copenhagen,
DK 2730 Herlev, Denmark
One of the main challenges in pharmacoepidemiology is
the assessment of the risk of rare but severe side effects. Since oral contraceptives were introduced in the early 1960s the most important concern has been the possible increased risk of thromboembolic disease
in users. Few drugs have been the object of such intensive epidemiological research, the outcome of which has provided clinicians with detailed information about risks not only of specific thrombotic diseases but also important non-contraceptive benefits from the pill.
The MICA study by Nicholas Dunn et al is an important reassuring
contribution to the assessment of the risk of acute myocardial infarction in users of oral contraceptives and is one of several recent
examples of large scale epidemiological studies conducted within a
relatively short time frame.
There are four important clinical messages from the study. Firstly, in
88% of cases the women had one or more classic cardiovascular risk
factors: 80% were smokers and not less than 73% of acute myocardial
infarction in women of reproductive age could be prevented if all women
stopped smoking. Secondly, the risk of infarct was not significantly
increased in users of combined oral contraceptives compared with
non-users. Thirdly, there was no significant difference in the risk of
acute myocardial infarct among users of different types of oral
contraceptives according to progestagen type. And, finally, adjustment
for relevant confounders in the multivariate analysis increased the
risk of the older "2nd generation" pills (with levonorgestrel)
and decreased the risk of the newer "3rd generation" pills (with
desogestrel or gestodene), suggesting a differential prescription of
older and newer pills to women at an anticipated increased risk of
thrombotic diseases.
At the same time, with recognition that epidemiological studies are the
strongest instrument to assess risks and benefits of different types of
drugs, the new study also illustrates that observational studies
(which for good reasons and in contrast with clinical trials are
not randomised) are very sensitive to different kind of bias; recall
bias and selection bias being the most important potential biases to
account for. In the MICA study the risk ratio between 3rd and 2nd
generation oral contraceptives was 1.14 on the basis of records
from general practitioners but 1.74 (70% higher) when the
estimate was based on the women's recall, suggesting that some kind of
recall bias was present, despite relevant measures taken to
diminish it.
The influence of selection of patients and controls in epidemiological
case-control studies is illustrated by the different measures of risk
of thrombotic diseases reached in different studies, even in the same
region during about the same period. The WHO multicentre study (198 cases) found a fivefold increased risk of acute myocardial infarction
in current users of oral contraceptives in Europe but an increase of
only 2.6-fold in women who had their blood pressure checked before
prescription.1 The transnational study (140 cases) found a
threefold increased risk in current users compared with hospital
controls but a twofold risk compared with community controls and
compared with users of oral contraceptives with 3rd generation
progestogens, implying significantly less risk than for those oral
contraceptives with 2nd generation
progestogens.2
An important challenge to the investigators of epidemiological studies
is to take relevant consideration of such biases and to try to assess
the possible impact of these methodological circumstances. This attempt
is the first opportunity for the lay press to effect a balanced message
to the public and for health authorities not to overreact to new
publications on rare side effects of oral contraceptives. Thereby
unnecessary new pill scares may be prevented. Unfortunately, reassuring
studies, such as the MICA study, are usually the object of less
attention than they deserve.
References
1.
World Health Organisation.
Collaborative study on cardiovascular disease and steroid hormone contraception. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study.
Lancet
1997;
349:
1202-1209.
2.
Lewis M, Heinemann LAJ, Spitzer WO, MacRae KD, Bruppacher R.
The use of oral contraceptives and the occurrence of acute myocardial infarction in young women.
Contraception
1997;
56:
129-140.
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(2000). Update in Women's Health. ANN INTERN MED
133: 808-814
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Dunn, N R, Arscott, A, Thorogood, M, Faragher, B, de Caestecker, L, MacDonald, T M, McCollum, C, Thomas, S, Mann, R D
(2000). Regional variation in incidence and case fatality of myocardial infarction among young women in England, Scotland and Wales. J. Epidemiol. Community Health
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(2000). Oral contraceptives and cardiovascular risk. DTB
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O'Brien, P.
(1999). Study confirms tendency towards lower risk of myocardial infarction with second generation oral contraceptives in UK. BMJ
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O'Brien, P. A
(1999). The third generation oral contraceptive controversy. BMJ
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[Full text]
Rapid Responses:
Read all Rapid Responses
- Large selection bias likely
- Rosemary Kirkman
bmj.com, 23 Jun 1999 [Full text] - MICA paper on oral contraceptives
- Paul O'Brien
bmj.com, 12 Jul 1999 [Full text] - Re: Large selection bias likely
- Nicholas Dunn
bmj.com, 17 Jul 1999 [Full text]
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