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Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke

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Abstract

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Background

Combined oral contraceptives (COCs) have been associated with an increased risk of arterial thrombosis, i.e. myocardial infarction or ischemic stroke. However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear.

Objectives

To estimate the risk of myocardial infarction or ischemic stroke in users compared with non‐users of different types, doses and generations of combined oral contraception.

Search methods

We searched electronic databases (MEDLINE (1966 to July 08, 2015), EMBASE (1980 to July 08, 2015), Popline (1970 to July 08, 2015) and LILACS (1985 to July 08, 2015) for eligible studies, without language restrictions.

Selection criteria

We included observational studies that recruited women in the reproductive age group (18 to 50 years) and compared the risk of myocardial infarction or ischemic stroke between users and non‐users of COCs.

Data collection and analysis

Two review authors independently selected relevant studies and extracted data. We pooled relative risks ()(combined odds ratios and one incidence rate ratio) and 95% confidence intervals (CIs) for myocardial infarction or ischemic stroke in users versus non‐users of COCs. We combined the outcomes of myocardial infarction and ischemic stroke and also analysed these outcomes separately. Analyses were stratified according to estrogen dose and progestagen type.

Main results

In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non‐users: relative risk (RR) 1.6 (95% CI 1.3‐1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen.

Authors' conclusions

This meta‐analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6‐fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

The risk of heart attack and stroke in women using birth control pills

Background

Since their introduction, combined oral contraceptive pills have become one of the most popular birth control methods. These pills contain two types of female hormones, estrogen and progestagen. When used correctly, the failure rate (i.e. the occurrence of unwanted pregnancy) is less than one per 100 women per year. Despite their reliability, oral contraceptive pills have been found to increase the risk of a blood clot forming in an artery, i.e. arterial thrombosis (heart attack or stroke). As arterial thrombosis is rare in young women, and as many types of oral contraceptive pills exist, the size of the risk is unclear. Furthermore, the effect of different types of progestagens or different doses of estrogen on the risk of arterial thrombosis is unknown.

Review question

In this Cochrane Review we aimed to assess the risk of arterial thrombosis in different types of oral contraceptive pills. To do this, we searched the literature on July 8, 2015 for all studies that assessed the risk of arterial thrombosis associated with oral contraceptive pills in women under the age of 50 years.

Study characteristics

In total, 28 articles on 24 unique studies met the inclusion criteria.

Key results

Our results showed that the overall risk of arterial thrombosis was was 1.6‐fold increased in women using oral contraceptive pills compared with women who did not use oral contraceptive pills. The risk did not vary clearly according to progestagen type. However, we found that the risk of arterial thrombosis seemed to be twice as high in women taking pills with higher doses of estrogen. Also, the risk of other side effects of oral contraceptive pills (such as a blood clot in a vein‐venous thrombosis) should be considered before any type of oral contraceptive pill is prescribed. It is likely that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception.

Quality of the evidence

The overall quality of evidence in this review was moderate. Most studies (22 out of 28) correctly confirmed that patients had been diagnosed with arterial thrombosis. However, only four studies also checked that the type of pill a patient had been using was reported correctly. In addition, only half of the studies ensured that the correct comparisons were made between patients with and patients without arterial thrombosis. Also of importance is the fact that the analysis on progestagen type was based on few studies only.

Authors' conclusions

Implications for practice

As all oral contraceptive preparations are equally effective for preventing unwanted pregnancies (Hardman 2009; van Hylckama Vlieg 2009), it is important that only the safest preparations are prescribed. The results of our meta‐analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6‐fold increased in women using COCs. The risk was highest for pills containing ≥ 50 µg of estrogen.The risk of myocardial infarction or ischemic stroke did not differ clearly between progestogen generation in combination with estrogens However, COCs are especially known to increase the risk of venous thrombosis, and this risk should be kept in mind when counselling women about their choice of contraception (de Bastos 2014).When combined with the results of studies on the risk of venous thrombosis in COC users, it is likely that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of combined oral hormonal contraception.

Implications for research

The purpose of this meta‐analysis was to assess the risk of myocardial infarction or ischemic stroke in women using oral forms of hormonal contraception. However, there are also a number of (newer) non‐oral hormonal contraceptive preparations, such as the levonorgestrel‐releasing intrauterine device, transdermal contraceptive patches, subcutaneous hormonal implants and the vaginal ring. As yet, only a very small number of studies have assessed the risk of myocardial infarction or ischemic stroke in women using these preparations. In the coming years, information on (thrombotic) side‐effects of these preparations should be collected and analysed, so that the associated risk of myocardial infarction or ischemic stroke, if any, can be quantified.

For many women, such as the women included in the studies in our meta‐analysis, it is too late to prevent a first episode of myocardial infarction or ischemic stroke. However, advising women with a first myocardial infarction or ischemic stroke to discontinue the use of hormonal preparations seems important to prevent a recurrent event. To our knowledge, no studies have specifically compared the risk of recurrent myocardial infarction or ischemic stroke in women who continued or discontinued the use of oral contraceptive preparations after a first arterial event. The two studies to answer this question for venous thrombosis found that all oral hormonal preparations were associated with an increased risk of recurrent venous thrombosis compared with no hormone use (Christiansen 2005; Christiansen 2010). The only preparation that was not associated with an increased risk was the levonorgestrel‐releasing intrauterine device. It is possible that the levonorgestrel‐releasing intrauterine device is also a safe option for women after a first arterial thrombotic event, as, from the small amount of available research, this preparation does not seem to increase the risk of a first myocardial infarction or ischemic stroke (Lidegaard 2012b). However, large studies on women using a levonorgestrel‐releasing intrauterine device need to be performed before this preparation is recommended without reservation.

Background

Description of the condition

Worldwide, myocardial infarction and ischemic stroke are two of the most important causes of morbidity and mortality (WHO 2013). It is estimated that over 17 million people die from cardiovascular diseases annually, with over 80% of deaths occurring in low‐ and middle‐income countries (Nabel 2012). Myocardial infarction most often occurs when an atherosclerotic plaque (a collection of fatty acids, fibrous tissue and leukocytes) ruptures in the wall of a coronary artery. The plaque contents obstruct the artery and deprive the downstream part of the heart muscle of oxygen (Nabel 2012). This can cause permanent cell damage or necrosis and leads to heart failure, stroke or death in up to 10% of cases (Brieger 2009; Roe 2010).

Ischemic stroke is characterized by brain ischemia due to the obstruction of a cerebral artery (Caplan 2009). As in myocardial infarction, a cerebral artery can be obstructed due to the rupture of an atherosclerotic plaque. Alternatively, a thrombus can embolize from elsewhere in the body and become lodged in the cerebral vasculature (Caplan 2009). The affected part of the brain rapidly loses function, leading to both transient and permanent disabilities such as loss of speech and movement (Di Carlo 2003).

The most important risk factors for myocardial infarction and ischemic stroke are hyper cholesterolemia, hypertension, diabetes and smoking (Wilson 1998). These risk factors generally accumulate over time, explaining why most patients with a cardiovascular event are aged 50 years or older (Berry 2012). Nevertheless, there are also risk factors that can contribute to myocardial infarction or ischemic stroke in younger (female) individuals. Studies in young women have shown an association between combined oral contraception use and an increased risk of myocardial infarction and ischemic stroke (Zakharova 2011). However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of combined oral contraceptive (COC) preparations remain unclear.

Description of the intervention

COCs are the most commonly used reversible form of contraception in developed countries (United Nations 2011). They contain an estrogen and a progestagen that are usually taken together in one pill for the first 21 days of every menstrual cycle, followed by a pill‐free week (Speroff 2011). COCs prevent ovulation, mainly by suppressing the surge in luteinizing hormone (due to the progestagen content) (Speroff 2011). With full compliance, the failure rate (i.e. the occurrence of unwanted pregnancy) is less than one per 100 women per year (Trussell 2011).

How the intervention might work

COCs are associated with an increase in many coagulation factors (e.g. factor VII, VIII, X), increased activity of the fibrinolytic inhibitors Plasminogen Activator Inhibitor (PAI)‐1 and PAI‐2 and a reduced anticoagulant response (activated protein C resistance) (Tchaikovski 2010). Research has recently found hypercoagulability to be an important determinant of atherogenesis and atherosclerosis (Borissoff 2011), which in turn precedes myocardial infarction and ischemic stroke. In addition, COCs have been associated with increases in triglycerides, Low Density Lipoprotein cholesterol and insulin levels, and a reduced glucose tolerance (Godsland 1990), which are all well known risk factors for arterial cardiovascular disease (Wilson 1998).

Why it is important to do this review

In order to reduce the harmful thrombotic side‐effects, the dose of estrogen in COCs has been gradually reduced from 150 µg in the first preparations to ≤ 30 µg today (Speroff 2011). In addition to preparations with so‐called 'first generation' progestagens lynestrenol and norethisterone, preparations containing second (levonorgestrel and norgestrel) or third generation progestagens (desogestrel and gestodene) and preparations containing drospirenone were developed in an attempt to improve the cardio‐metabolic profile of COCs (Godsland 1990; Bringer 1992; Badimon 1999; Krattenmacher 2000). Still, results of studies on the risk of myocardial infarction and ischemic stroke associated with various types of COCs are conflicting. As over 100 million women use COCs worldwide (WHO 2004) and all combined preparations are equally effective for the prevention of unwanted pregnancies (Lawrie 2011), the issue of safety is paramount. Therefore, it is important to obtain a systematic overview of all available evidence on this topic in order to advise women as to the safest choice of combined oral contraception with regards to the risk of myocardial infarction and ischemic stroke.

Objectives

  1. To estimate the risk of myocardial infarction and ischemic stroke in combined oral contraception users compared with non‐users.

  2. To compare the risk of myocardial infarction and ischemic stroke associated with the three generations of COCs, as well as with preparations containing drospirenone or cyproterone acetate.

  3. To compare the effect of varying doses of estrogen and types of progestagen in COCs on the risk of myocardial infarction and ischemic stroke.

Methods

Criteria for considering studies for this review

Types of studies

Myocardial infarction and ischemic stroke are potential side effects of COC use. Previous research has suggested that results of observational studies are credible when studying side effects of medication(Vandenbroucke 2004). This was supported by a meta‐analysis that showed no difference between the risk of side‐effects assessed in meta‐analyses of experimental data and the risk of side‐effects assessed in meta‐analyses of observational data(Golder 2011). Therefore in this Cochrane Review we included observational studies with a cohort, case‐control or nested case‐control design and, if available, data from randomised controlled trials (RCTs).

Types of participants

The participants were women in the reproductive age group (18 to 50 years) who either used or did not use COCs. We excluded studies on women using postmenopausal hormone therapy, non‐oral contraceptives or progestagen‐only contraceptives.

Types of interventions

We compared the risk of myocardial infarction and ischemic stroke between combined oral contraception users and non‐users. Both previous combined oral contraception users and never users were considered to be non‐users. The risk of myocardial infarction and ischemic stroke was assessed for different types of COC preparations. We categorized COCs according to their generation (progestagens). We classified preparations containing lynestrenol or norethindrone as first generation preparations, levonorgestrel and norethisterone acetate as second generation progestagens, and desogestrel and gestodene as third generation preparations. In addition, we categorized COCs separately according to the dose of estrogen and the type of progestagen used.

Types of outcome measures

The outcome measures of interest were objectively diagnosed fatal or non‐fatal first myocardial infarction or ischemic stroke. We classified a myocardial infarction as objectively confirmed if diagnosed based on a medical examination and pain assessment combined with an electrocardiogram (ECG), serum cardiac biomarkers or other specified strict diagnostic criteria of myocardial infarction, or by autopsy examination. Ischemic stroke was classified as objectively confirmed if a sudden onset focal neurological deficit was diagnosed on the basis of a medical history and neurological examination combined with brain imaging, or by autopsy examination.

We quantified the risk of developing either myocardial infarction or ischemic stroke in COC users compared with non‐users by obtaining crude numbers of users and non‐users of combined oral contraception, and crude numbers of women with and women without an arterial thrombotic event. We combined these numbers to compute an overall relative risk of myocardial infarction or ischemic stroke in COC users.

Primary outcomes

  • Fatal or non‐fatal arterial thrombosis (i.e. myocardial infarction or ischemic stroke).

Secondary outcomes

  • Fatal or non‐fatal myocardial infarction.

  • Fatal or non‐fatal ischemic stroke.

Search methods for identification of studies

We created the search in association with an expert librarian (C. Manion, Cochrane).

Electronic searches

We searched the following databases: MEDLINE (1966 to July 08, 2015), EMBASE (1980 to July 08, 2015), Popline (1970 to July 08, 2015) and LILACS (1985 to July 08, 2015). The study search was performed without language restrictions.

Searching other resources

The references of the selected studies and of reviews were additionally checked in case we did not capture any relevant studies through our search strategy.

Data collection and analysis

We used the study results to compare the relative risk of myocardial infarction and ischemic stroke between users and non‐users of COCs, and between women using different types and doses of COCs. Most studies included women without oral contraception or women who use preparations containing levonorgestrel with 30 µg of ethinylestradiol as a reference group. Standard meta‐analytic techniques were used, a random effect model being set as default.

Selection of studies

Two review authors (REJR, FMH) independently evaluated the title and abstract of all studies retrieved from the search strategy. This was done using standard piloted forms and specific inclusion and exclusion criteria. We resolved any disagreements by consensus and consulted a third review author (OMD) if necessary.

Data extraction and management

Two review authors (REJR and FMH) independently extracted data using standard, piloted data extraction forms and entered data into Review Manager (RevMan). We resolved all disagreements by consensus.

Assessment of risk of bias in included studies

Our 'Risk of bias' assessment was equipped for observational studies and adapted from the Newcaste Ottowa scale. We examined the risk of bias in the included observational studies based on four aspects that may affect the association between the exposure (COCs) and the outcome (myocardial infarction and ischemic stroke).

Firstly, exposure to combined oral contraception had to be confirmed through a prescription database in order for the risk of bias to be classified as 'low'. We classified other, less objective, methods such as interviews and questionnaires as a 'high' risk of bias, as research has shown that women have difficulty accurately recalling the type of preparations they used (Nischan 1993; Norell 1998).

Secondly, the diagnosis of a myocardial infarction or ischemic stroke had to be ascertained by objective measures. We classified studies in which myocardial infarction had been diagnosed on the basis of an ECG, serum cardiac biomarkers or other specified strict diagnostic criteria of myocardial infarction, or by autopsy examination as having a low risk of bias. For ischemic stroke these criteria were a neurological examination combined with brain imaging or other specified strict diagnostic criteria of ischemic stroke, or autopsy examination.

In cohort studies, loss to follow‐up can lead to biased risk estimates. We classified studies with < 10% loss to follow‐up as having a low risk of bias.

Finally, in case‐control selection, the selection of controls affects the validity of the results. We classified case‐control studies including controls from the source population of the cases (i.e. controls from the same neighbourhood as the cases who would most likely have been admitted to the same hospital as the cases if they had developed myocardial infarction or ischemic stroke) as low risk of bias (Grimes 2005).

As myocardial infarction and ischemic stroke are side effects of using COCs, and it is unethical to perform a RCT for side effects alone, we did not anticipate finding any RCTs on this topic. However, if such studies were found, we would have assessed the risk of bias according to recommended principles (Higgins 2011). We did not use an aggregate 'Risk of bias' score as this is generally discouraged (Jüni 1999).

Two review authors (REJR, FMH) independently assessed the risk of bias using a standard piloted form. Both review authors are trained in Clinical Epidemiology and Study Methodology. We resolved any persistent disagreement by consensus or discussion with a third review author (OMD). We did not use the 'Risk of bias' assessment to accept or reject studies.

Measures of treatment effect

From each matched case‐control study (matched on age and calendar time) included , we extracted the crude number of women who were exposed to combined oral contraception, the crude number of women not exposed to combined oral contraception, the crude number of women with myocardial infarction or ischemic stroke and the crude number of women without myocardial infarction or ischemic stroke event. In addition we extracted the crude numbers of women in separate subgroups (i.e. different doses of estrogen, different types of progestagen). We used these numbers to calculate odds ratios for COC users versus non‐users at the study level . For one cohort study (Lidegaard 2012a) this matching assumption was not met, and we extracted adjusted estimates (incidence rate ratio).

Unit of analysis issues

Current use of COCs, stratified according to the dose of ethinylestradiol and the type of progestagen, was analysed in women without a history of myocardial infarction or ischemic stroke. Also we studied the effect of previous combined oral contraception use on the risk of cardiovascular disease if data were available.

Dealing with missing data

We only included participants with complete data on exposure to COCs and the outcomes myocardial infarction or ischemic stroke, or both.

Assessment of heterogeneity

For results from standard meta‐analytic techniques, we presented statistical measures of heterogeneity (Chi² test and I² statistics).

Assessment of reporting biases

We made an overview of possible reporting biases for each included study. In addition, for the overall comparison of COC users with non‐users, we performed sensitivity analyses according to the presence or absence of various types of bias.

Data synthesis

We combined data from studies with similar designs, interventions and outcome measures. For the analysis on use versus non‐use and the analysis at the level of estrogen generations, we performed a random effects meta‐analysis based on data that were adjusted for age and calendar time by design or by analysis. For one cohort study (Lidegaard 2012a) we first performed a fixed effect meta‐analysis based on risk estimates for various contraceptives from that study. The pooled analysis was subsequently used in the random effects meta‐analysis. For analyses with 5 or less studies, both fixed and random effect analyses are presented as, in this case, the between study variability cannot be estimated reliably.

The matched case‐control studies provided odds ratios. As these studies were matched on calendar time the odds ratios are a valid estimate of the incidence rate ratio (Knol 2008, Vandenbroucke 2012). Moreover, as the outcome is very rare, relative risks, incidence rate ratios and odds ratios will be similar. We used the term relative risk to denote the pooled effect, even though formally speaking, this consisted of odds ratios and an incidence rate ratio.

We initially aimed to perform a formal network analysis. However, this requires the use of raw data in case of multiple arm studies. Raw data can only be used if unadjusted estimates provide meaningful effect estimates, which was not the case for the cohort study mentioned above Lidegaard 2012a. We therefore applied standard random effects meta‐analysis techniques throughout the review.

Sensitivity analysis

The outcomes myocardial infarction and ischemic stroke were pooled as well as analysed separately. To explore heterogeneity, we performed sensitivity analyses according to funding source and risk of bias. We defined funding as any financial support for the study from pharmaceutical companies.

Results

Description of studies

In total, we identified 1182 unique publications by searching electronic databases and checking the reference lists of the selected articles. Of these, we excluded 1047 publications based on the title or abstract, or both, and excluded a further 107 articles after detailed assessment of the full text (Figure 1). Twenty‐eight articles reporting on 24 separate studies met the inclusion criteria and were eligible for analysis. Heinemann 1998 and Lewis 1997 both presented results from the 'Transnational Study on Oral Contraceptives and the Health of Young Women' study, with Heinemann 1998 reporting on ischemic stroke and Lewis 1997 reporting on myocardial infarction. Similarly, van Kemmeren 2002 reported on ischemic stroke in the RATIO, whereas Tanis 2001 presented the data on myocardial infarction. Shapiro 1979 and Slone 1981 reported different analyses of the same study from the USA. The two articles by Mann 1975a and Mann 1975b reported on different data from a single British study. Finally, the article by Sidney 1998 on myocardial infarction described data from the Kaiser Permanente study and the University of Washington study, from which the risk of ischemic stroke is separately reported in Pettiti 1996 and Schwartz 1997. Thirteen studies were performed in Europe, eight in the USA and three studies in several countries around the world.


Study flow diagram.

Study flow diagram.

The eligible publications included one cohort study (Lidegaard 2012a), 22 case‐control studies and one nested case‐control study. We did not find any RCTs on this topic. Sixteen of the 28 articles reported on the relationship between COCs and myocardial infarction. Eleven articles reported on ischemic stroke and one study assessed both the risk of myocardial infarction and the risk of ischemic stroke. All included articles were published between 1975 and 2010 and reported on data collected between 1968 and 2009. The pharmaceutical industry sponsored six of the 24 included studies.

Risk of bias in included studies

We have presented the risk of bias per publication in Figure 2. In total, only five studies confirmed the use of combined oral contraception through a prescription database and were classified as having a low risk of bias. All other papers assessed the exposure by questionnaire or interview only (high risk of bias).


Risk of bias in the 28 included articles (reporting on 24 included studies). Green: low risk; red: high risk; yellow: unclear risk.Regarding Lidegaard 2012a "Source population": not applicable as this was a population study.

Risk of bias in the 28 included articles (reporting on 24 included studies). Green: low risk; red: high risk; yellow: unclear risk.

Regarding Lidegaard 2012a "Source population": not applicable as this was a population study.

The outcomes myocardial infarction and ischemic stroke were ascertained by objective measures in 22 studies. Six studies had a high risk of bias as the diagnoses were not objectively confirmed.

The only cohort study that was included in this Cochrane Review had almost complete follow‐up and so was classified as having a low risk of bias. Follow‐up was not applicable to the other included articles as they all reported on case‐control studies.

Thirteen studies had a low risk of bias as they included control subjects from the same source population as the cases. The 15 other studies included hospital controls as control subjects which is associated with a high risk of bias.

Effects of interventions

Current versus none use

All 24 included studies assessed the risk of myocardial infarction or ischemic stroke in current versus non‐users of combined oral contraception (Table 1). We performed a standard random‐effects meta‐analysis to assess the risk of myocardial infarction or ischemic stroke in these groups. (Figure 3) COC users were at increased risk of myocardial infarction or ischemic stroke compared with non‐users: relative risk 1.6 (95% CI 1.3‐1.9).These RRs were similar for myocardial infarction ( 1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9).


Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users.

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users.

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Table 1. Type of outcome in included studies

Study

P

ublication year

Study design

Outcomea

Adam 1981.

1981

Case control

Myocardial infarction

Aznar 2004

2004

Case control

Ischemic stroke

Chang 1999

1999

Case control

Ischemic stroke

Dunn 1999

1999

Case control

Myocardial infarction

Heinemann 1998/Lewis 1997.

1998/1997

Case control

Both

Jick 1978

1978

Case control

Myocardial infarction

Kemmeren 2002/Tanis 2001

2002/2001

Case control

Both

Krueger 1980

1981

Case control

Myocardial infarction

La Vecchia 1987

1987

Case control

Myocardial infarction

Lidegaard 2012a

2012

Cohort

Both

MacClellan 2007.

2007

Case control

Ischemic stroke

Mann 1975a/Mann 1975b

1975/1976

Case control

Myocardial infarction

Mann 1975b

1975

Case control

Myocardial infarction

Martinelli 2006

2006

Case control

Ischemic stroke

Nightingale 2004

2004

Nested case control

Ischemic stroke

Owen‐Smith 1998

1998

Case control

Ischemic stroke

Pettiti 1996

1997

Case control

Ischemic stroke

Pezzini 2007

2007

Case control

Ischemic stroke

Rosenberg 1976a

1976

Case control

Myocardial infarction

Rosenberg 2001

2001

Case control

Myocardial infarction

Schwartz 1997

1998

Case control

Ischemic stroke

Sidney 1998

1998

Case control

Myocardial infarction

Shapiro 1979/Slone 1981

1981/1981

Case control

Myocardial infarction

Tzourio 1995

1995

Case control

Ischemic stroke

aDenotes both myocardial infarction and ischemic stroke.

Progestagen generation

Overall, eight studes assessed the risk of myocardial infarction or ischemic stroke for different generations of COC preparations (Table 2, Figure 4). The results of the meta‐analysis showed that first generation preparations were not clearly associated with an increased risk of myocardial infarction or ischemic stroke: pooled RR 1.2 (95% CI 0.8 to 1.9) compared with non‐use. The pooled relative risks for second generation versus non‐use and third generation versus non‐use were 1.1 (95% CI 0.8‐1.7) and 1.1 (95% CI 0.7‐1.7) respectively.


Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per generation

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per generation

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Table 2. Included studies with data on COC generation

Study

Design

Outcome

Non‐use

Event (n)/Total (n)

1st generation

Event (n)/Total (n)

2nd generation

Event (n)/Total (n)

3rd generation

Event (n)/Total (n)

Dunn 1999

Case‐control

Myocardial infarction

386/1853

20/139

20/81

Kemmeren 2002

Case‐control

Ischemic stroke

101/669

7/38

52/225

32/142

Lewis 1997

Case‐control

Ischemic stroke

125/397

14/28

27/62

8/41

Lidegaard 2012a

Cohort

Both

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/3301

11/79

4/46

2/17

Schwartz 1998

Case‐control

Ischemic stroke

52/476

4/36

1/15

Sidney 1998

Case‐control

Myocardial infarction

255/1159

8/60

3/27

Tanis 2001

Case‐control

Myocardial infarction

146/714

11/42

59/232

20/130

Abbreviations: COC: combined oral contraceptives; n: number.
1st generation: preparations containing lynestrenol or norethisterone acetate.
2nd generation: preparations containing levonorgestrel.
3rd generation: preparations containing desogestrel or gestodene.

* Adjusted effect estimates extracted

Estrogen dose

Seven studies provided data on the risk of myocardial infarction or ischemic stroke according to the dose of estrogen (Table 3 , Figure 5). The risk of myocardial infarction or ischemic stroke increased with increasing doses of estrogen (RR 1.6, 95% CI 1.4 to 1.8) for preparations containing 20 µg of estrogen (RR 2.0, 95% CI 1.4 to 3.0) for 30 to 49 µg of estrogen and RR 2.4 (95% CI 1.8 to 3.3) for ≥ 50 µg of estrogen.


Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified by estrogen dose

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified by estrogen dose

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Table 3. Included studies with data on oestrogen dose

Study

Design

Outcome

Non‐use

Event (n)/Total (n)

20 µg E2

Event (n)/Total (n)

30 to 49 µg E2

Event (n)/Total (n)

≥ 50 µg E2

Event (n)/Total (n)

Chang 1999

Case‐control

Ischemic stroke

42/188

9/23

Heinemann 1998

Case‐control

Ischemic stroke

96/353

15/38

Lidegaard 2012a

Cohort

Both

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/3301

4/7

Shapiro 1979

Case‐control

Myocardial infarction

205/1812

18/107

Sidney 1998

Case‐control

Myocardial infarction

255/1159

2/7

Tzourio 1995

Case‐control

Ischemic stroke

25/135

2/7

30/76

8/15

Abbreviations: µg: micrograms; E2: ethinylestradiol; n: number.

* Adjusted effect estimates extracted

Progestagen type

Finally, seven studies assessed the risk of myocardial infarction or ischemic stroke for various types of progestagen (Table 4, Figure 6). Of note, only few studies contributed data per progestagen type (maximum 5 studies, minimum 1 study).


Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per prosgestagen type

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per prosgestagen type

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Table 4. Studies including data on progestagen type

Study

Design

Outcome

Event (n)/Total (n)

Non‐use

Norethindron

Levonorgestrel

Norethisterone acetate

Desogestrel

Gestodene

Norgestimate

Drospirenone

Cyproterone acetate

Dunn 1999

Case‐control

Myocardial infarction

386/1853

18/123

2/16

9/46

11/35

Kemmeren 2002

Case‐control

Ischemic stroke

101/669

52/225

Lewis 1997

Case‐control

Myocardial infarction

125/397

8/41

Lidegaard 2012a

Cohort

Both

*

*

*

*

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/ 3301

11/79

4/46

Schwartz 1997

Case‐control

Ischemic stroke

156/ 921

10/64

4/24

Sidney 1998

Case‐control

Myocardial infarction

255/ 1159

8/60

3/27

Abbreviations: n: number.

* Adjusted effect estimates extracted

Check for consistency

Most analyses showed evidence of considerable heterogeneity. The overall analyses for use versus non‐use showed clear evidence of between study heterogeneity beyond chance (i2 78%).

Sensitivity analysis

We performed sensitivity analyses for the risk of myocardial infarction or ischemic stroke in users compared with non‐users of combined oral contraception according to funding source, and according to the risk of bias. Risk estimates were similar in studies sponsored by a pharmaceutical company: RR 1.6 (95% CI 0.9 to 2.4) versus non‐industry studies RR 1.5 (95% CI 1.2 to 1.9). Also no clear difference was found between studies with and without a objective diagnostic measures (p=0.3 from meta‐regression), or between studies with and without a biased selection of control subjects (p=0.2).

Discussion

Summary of main results

In this Cochrane Review, we performed a meta‐analysis of 28 publications to assess the risk of myocardial infarction or ischemic stroke in women using COCs. Overall, the risk of myocardial infarction or ischemic stroke was 1.6 fold increased in women that used COC compared with non‐users. This risk did also not vary according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen.

Overall completeness and applicability of the evidence

We have discussed this topic under the 'Potential biases in the review process' section.

Quality of the evidence

We have discussed this topic under the 'Potential biases in the review process' section and presented it in Figure 2.

Potential biases in the review process

We mostly included raw data for the analysis in our review. Therefore, we cannot rule out that our results may have been confounded by factors that influence both the type of COC preparation that is prescribed and the risk of myocardial infarction or ischemic stroke (e.g. age, body mass index, smoking and calendar time). However, all except one (Lidegaard 2012a) of the included studies were case‐control studies, in which adjustment for age and calendar time is usually dealt with by design (matching). In addition, body mass index and smoking are only weakly associated with COC use and so we do not expect that the lack of adjustment for these variables will have introduced important bias. Indeed, in the six studies that presented both crude and (extensively) adjusted risk estimates for myocardial infarction or ischemic stroke, adjustment only affected the results in two instances (Table 5). Furthermore, if certain types of COCs had been preferentially prescribed to 'less healthy' women (e.g. obese women or smokers) who have a higher risk of myocardial infarction of ischemic stroke, the number of arterial thrombotic events associated with these preparations would have been overestimated. As our results showed no increased risk of myocardial infarction or ischemic stroke in women using COC preparations, any further reduction in this risk estimate due to elimination of confounding would not change the conclusion of our meta‐analysis.

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Table 5. Adjusted risk of myocardial infarction or ischemic stroke in COC users versus non‐users per study

Study

Crude OR (95% CI)

Adjusted OR (95% CI)

Adjustment variables per study

Heinemann 1998

1.8 (1.3 to 2.5)

2.8 (1.8 to 4.5)

Age, hypertension, body mass index, lipid levels, diabetes, smoking,

alcohol, family history of stroke, duration of COC use, study centre

La Vecchia 1987

2.1 (0.7 to 7.1)

1.8 (0.3 to 11.5)

Age, geographic area, marital status, education, social class, smoking,

alcohol and coffee consumption, parity, age at menopause, diabetes,

hypertension, obesity, hyperlipidemia, family history of ischemic heart disease

Martinelli 2006

2.3 (1.5 to 3.8)

2.3 (1.4 to 3.8)

Age, educational level, hypertension, hypercholesterolemia, obesity, smoking

Nightingale 2004

1.6 (0.9 to 2.9)

2.3 (1.2 to 4.6)

Heart disease, diabetes, hypertension, previous venous thrombosis, migraine,

alcohol, smoking

Owen‐Smith 1998

2.9 (1.0 to 8.7)

2.9 (0.9 to 9.6)

Social class, smoking status, history of hypertension

Pettiti 1996

1.0 (0.5 to 1.9)

1.2 (0.5 to 2.6)

Hypertension, diabetes, smoking, race, body mass index

Abbreviations: OR: odds ratio; COC: combined oral contraception.
For all other studies, the crude OR or the adjusted OR, or both, were not presented in the manuscript.

A second point that warrants comment, is the lack of a generally accepted way of classifying oral contraceptives. For instance, in some studies, norgestimate is classified as a third generation preparation, whereas most studies only consider desogestrel and gestodene to be third generation preparations. In this meta‐analysis, we chose not to classify norgestimate as a third generation preparation, but only to include desogestrel and gestodene in this definition. However, as we did not find any large differences between the risk of myocardial infarction or ischemic stroke associated with desogestrel, gestodene and norgestimate in the analysis of each progestagen type separately , we do not expect that this choice has greatly influenced our results.

A third point is that some analyses (especially the analyses based on progestagen type) are based on very few studies only. It goes without saying that these results are therefore accompanied by much uncertainty.

Finally, in the analysis on estrogen dose, we did not take the type of progestagen into account. The reason for this was that most studies that provided data on the dose of estrogen did not specify the type of progestagen. However, we consider it unlikely that this classification greatly influenced our results, as preparations containing ≥ 50 µg of estrogen almost always contain levonorgestrel and we did not find this preparation to be associated with an increased risk of myocardial infarction or ischemic stroke in the analysis according to generation (second generation) or the analysis according to progestagen type. For the same reason, we could not take the estrogen dose into account in the analysis on progestagen type. However, as most preparations contained 30 to 49 µg of estrogen (Table 3) a large confounding effect of estrogen dose seems unlikely.

Agreements and disagreements with other studies or reviews

A previous systematic review on the relationship between COCs and myocardial infarction or ischemic stroke found the risk of myocardial infarction or ischemic stroke to be increased with COC use (Plu‐Bureau 2013). However, the review only included studies that were set up after 1990 and only assessed preparations containing low doses of estrogen, third generation progestagens (in which norgestimate was included) or progestin‐only contraceptives, making the two reviews incomparable. Four previous meta‐analyses, two on the risk of myocardial infarction or ischemic stroke (Baillargeon 2005; Peragallo‐Urrutia 2013), one on the risk of myocardial infarction alone (Khader 2003) and one on the risk of ischemic stroke alone (Gillum 2000), similarly found an increased risk in combined oral contraception users compared with non‐users. However, the inclusion criteria for these studies were less strict than for our current meta‐analysis, e.g. defining COC use within the past year as current use, including studies with non‐incident arterial events, analyzing studies with women up to 60 years of age, and including studies that did not present crude numbers of exposed or diseased cases and controls. To our knowledge, our Cochrane Review is the first meta‐analysis to assess the risk of incident myocardial infarction or ischemic stroke in women < 50 years of age who used COCs at or within one month before the date of inclusion.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias in the 28 included articles (reporting on 24 included studies). Green: low risk; red: high risk; yellow: unclear risk.Regarding Lidegaard 2012a "Source population": not applicable as this was a population study.
Figures and Tables -
Figure 2

Risk of bias in the 28 included articles (reporting on 24 included studies). Green: low risk; red: high risk; yellow: unclear risk.

Regarding Lidegaard 2012a "Source population": not applicable as this was a population study.

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users.
Figures and Tables -
Figure 3

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users.

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per generation
Figures and Tables -
Figure 4

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per generation

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified by estrogen dose
Figures and Tables -
Figure 5

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified by estrogen dose

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per prosgestagen type
Figures and Tables -
Figure 6

Effect of myocardial infarction and/or stroke in oral contraceptive users versus non‐users stratified per prosgestagen type

Table 1. Type of outcome in included studies

Study

P

ublication year

Study design

Outcomea

Adam 1981.

1981

Case control

Myocardial infarction

Aznar 2004

2004

Case control

Ischemic stroke

Chang 1999

1999

Case control

Ischemic stroke

Dunn 1999

1999

Case control

Myocardial infarction

Heinemann 1998/Lewis 1997.

1998/1997

Case control

Both

Jick 1978

1978

Case control

Myocardial infarction

Kemmeren 2002/Tanis 2001

2002/2001

Case control

Both

Krueger 1980

1981

Case control

Myocardial infarction

La Vecchia 1987

1987

Case control

Myocardial infarction

Lidegaard 2012a

2012

Cohort

Both

MacClellan 2007.

2007

Case control

Ischemic stroke

Mann 1975a/Mann 1975b

1975/1976

Case control

Myocardial infarction

Mann 1975b

1975

Case control

Myocardial infarction

Martinelli 2006

2006

Case control

Ischemic stroke

Nightingale 2004

2004

Nested case control

Ischemic stroke

Owen‐Smith 1998

1998

Case control

Ischemic stroke

Pettiti 1996

1997

Case control

Ischemic stroke

Pezzini 2007

2007

Case control

Ischemic stroke

Rosenberg 1976a

1976

Case control

Myocardial infarction

Rosenberg 2001

2001

Case control

Myocardial infarction

Schwartz 1997

1998

Case control

Ischemic stroke

Sidney 1998

1998

Case control

Myocardial infarction

Shapiro 1979/Slone 1981

1981/1981

Case control

Myocardial infarction

Tzourio 1995

1995

Case control

Ischemic stroke

aDenotes both myocardial infarction and ischemic stroke.

Figures and Tables -
Table 1. Type of outcome in included studies
Table 2. Included studies with data on COC generation

Study

Design

Outcome

Non‐use

Event (n)/Total (n)

1st generation

Event (n)/Total (n)

2nd generation

Event (n)/Total (n)

3rd generation

Event (n)/Total (n)

Dunn 1999

Case‐control

Myocardial infarction

386/1853

20/139

20/81

Kemmeren 2002

Case‐control

Ischemic stroke

101/669

7/38

52/225

32/142

Lewis 1997

Case‐control

Ischemic stroke

125/397

14/28

27/62

8/41

Lidegaard 2012a

Cohort

Both

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/3301

11/79

4/46

2/17

Schwartz 1998

Case‐control

Ischemic stroke

52/476

4/36

1/15

Sidney 1998

Case‐control

Myocardial infarction

255/1159

8/60

3/27

Tanis 2001

Case‐control

Myocardial infarction

146/714

11/42

59/232

20/130

Abbreviations: COC: combined oral contraceptives; n: number.
1st generation: preparations containing lynestrenol or norethisterone acetate.
2nd generation: preparations containing levonorgestrel.
3rd generation: preparations containing desogestrel or gestodene.

* Adjusted effect estimates extracted

Figures and Tables -
Table 2. Included studies with data on COC generation
Table 3. Included studies with data on oestrogen dose

Study

Design

Outcome

Non‐use

Event (n)/Total (n)

20 µg E2

Event (n)/Total (n)

30 to 49 µg E2

Event (n)/Total (n)

≥ 50 µg E2

Event (n)/Total (n)

Chang 1999

Case‐control

Ischemic stroke

42/188

9/23

Heinemann 1998

Case‐control

Ischemic stroke

96/353

15/38

Lidegaard 2012a

Cohort

Both

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/3301

4/7

Shapiro 1979

Case‐control

Myocardial infarction

205/1812

18/107

Sidney 1998

Case‐control

Myocardial infarction

255/1159

2/7

Tzourio 1995

Case‐control

Ischemic stroke

25/135

2/7

30/76

8/15

Abbreviations: µg: micrograms; E2: ethinylestradiol; n: number.

* Adjusted effect estimates extracted

Figures and Tables -
Table 3. Included studies with data on oestrogen dose
Table 4. Studies including data on progestagen type

Study

Design

Outcome

Event (n)/Total (n)

Non‐use

Norethindron

Levonorgestrel

Norethisterone acetate

Desogestrel

Gestodene

Norgestimate

Drospirenone

Cyproterone acetate

Dunn 1999

Case‐control

Myocardial infarction

386/1853

18/123

2/16

9/46

11/35

Kemmeren 2002

Case‐control

Ischemic stroke

101/669

52/225

Lewis 1997

Case‐control

Myocardial infarction

125/397

8/41

Lidegaard 2012a

Cohort

Both

*

*

*

*

*

*

*

*

Rosenberg 2001

Case‐control

Myocardial infarction

591/ 3301

11/79

4/46

Schwartz 1997

Case‐control

Ischemic stroke

156/ 921

10/64

4/24

Sidney 1998

Case‐control

Myocardial infarction

255/ 1159

8/60

3/27

Abbreviations: n: number.

* Adjusted effect estimates extracted

Figures and Tables -
Table 4. Studies including data on progestagen type
Table 5. Adjusted risk of myocardial infarction or ischemic stroke in COC users versus non‐users per study

Study

Crude OR (95% CI)

Adjusted OR (95% CI)

Adjustment variables per study

Heinemann 1998

1.8 (1.3 to 2.5)

2.8 (1.8 to 4.5)

Age, hypertension, body mass index, lipid levels, diabetes, smoking,

alcohol, family history of stroke, duration of COC use, study centre

La Vecchia 1987

2.1 (0.7 to 7.1)

1.8 (0.3 to 11.5)

Age, geographic area, marital status, education, social class, smoking,

alcohol and coffee consumption, parity, age at menopause, diabetes,

hypertension, obesity, hyperlipidemia, family history of ischemic heart disease

Martinelli 2006

2.3 (1.5 to 3.8)

2.3 (1.4 to 3.8)

Age, educational level, hypertension, hypercholesterolemia, obesity, smoking

Nightingale 2004

1.6 (0.9 to 2.9)

2.3 (1.2 to 4.6)

Heart disease, diabetes, hypertension, previous venous thrombosis, migraine,

alcohol, smoking

Owen‐Smith 1998

2.9 (1.0 to 8.7)

2.9 (0.9 to 9.6)

Social class, smoking status, history of hypertension

Pettiti 1996

1.0 (0.5 to 1.9)

1.2 (0.5 to 2.6)

Hypertension, diabetes, smoking, race, body mass index

Abbreviations: OR: odds ratio; COC: combined oral contraception.
For all other studies, the crude OR or the adjusted OR, or both, were not presented in the manuscript.

Figures and Tables -
Table 5. Adjusted risk of myocardial infarction or ischemic stroke in COC users versus non‐users per study