K S Joseph, Lucie Blais, Pierre Ernst, Samy Suissa
Abstract
Objective - To assess the potentially increased risk of death or near death from asthma in asthmatic patients with psychosis
Design - Case-control study
Setting - The computerised health databases of the Canadian province of Saskatchewan
Subjects - 131 cases of death or near death from asthma identified within a cohort of asthmatic patients; 3,930 matched non-cases
Exposure and outcome measures - The exposure of interest was the use of major tranquillisers in the period before an outcome event. Outcomes included death or near death from asthma
Results - Crude analyses showed that asthmatic patients who had used major tranquillisers in the previous 12 months were at a 3.2 (95% confidence interval 1.4 to 7.5) times greater risk of death or near death from asthma than asthmatic patients who did not use major , tranquillisers. Past users of major tranquillisers who had recently discontinued use were at a particularly high risk (relative risk 6.6; 2.5 to 17.6). Adjustment for use of antiasthma drugs and other confounders abolished this excess risk.
Conclusion - Asthmatic patients who use major tranquillisers seem to be at an increased risk of death or near death from asthma. Physicians treating asthmatic patients with a history of use of major tranquillisers should exercise greater caution with regard to management of such patients
Department of Epidemiology and Biostatistics McGill Pharmacoepidemiology Unit McGill University Montreal Quebec Canada H3A 1A2 Dr K S Joseph research fellow Lucie Blais doctoral scholar Pierre Ernst associate professor Samy Suissa associate professor
Correspondence to Dr K S Joseph Royal Victoria Hospital Division of Clinical Epidemiology 687 Pine Avenue West Ross 4 Montreal Quebec, Canada H3A 1A1
Reprint requests to Dr S Suissa Royal Victoria Hospital Division of Clinical Epidemiology 687 Pine Avenue West Ross 4 Montreal Quebec, Canada H3A 1A1
Walter O Spitzer, Michael A Lewis, Lothar A J Heinemann, Margaret Thorogood, Kenneth D MacRae on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women
Objective - To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism.
Design - Matched case-control study.
Setting - 10 centres in Germany and United Kingdom.
Subjects - Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1,772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting.
Main outcome measures - Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables.
Results - Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4 0 (3.1 to 5.3); for second generation products (low dose ethinyloestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year. Conclusions - Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptive compared with users of second generation products.
Oral contraceptives have been linked with a small absolute increase in the incidence of vascular disease in many epidemiological studies. Several reviewers have weighed the evidence on the safety of early oral contraceptives and have concluded that their risks are balanced by benefits.[i-iv] Since their introduction, oral contraceptives have undergone considerable development intended to reduce the risk of adverse effects. In the 1970s second generation drugs were introduced that contained a lower dose of ethinyloestradiol, which it was believed would reduce the risk of vascular disease. More recently, third generation drugs were introduced that contained gonane progestogens - desogestrel, gestodene, and norgestimate.
Later events have led to a reappraisal of the safety of these third generation drugs. Results of a pharmacokinetic study of 22 women in Germany suggested that gestodene, but not desogestrel, may increase the risk of vascular events.[v,vi] This led the German regulatory authorities to alert doctors to drugs containing gestodene and to require an epidemiological study of vascular disease. In October 1995 unpublished results from three studies, including the one reported here, led the Committee on Safety of Medicines in the United Kingdom to warn doctors of a potentially increased risk of venous thromboembolism in users of oral contraceptives containing desogestrel or gestodene.
The transnational case-control study of oral contraceptives is a multinational study of oral contraceptives and vascular disease undertaken at the request of German regulatory authorities in response to concern about gestodene. This first report has been prepared earlier than planned in response to the expressed needs of the medicines regulatory authorities in Europe and the wider medical community.
GENERAL PLAN AND DESIGN
Our design and all definitions, questionnaires, and field operations were virtually identical to those of the case-control study of the World Health Organisation Human Reproduction Unit,[vii] which was under way as we started. This was done to allow the results to be combined at a later date if necessary. The transnational project encompasses three simultaneous case-control studies, with respective outcomes of deep vein thrombosis and pulmonary embolism (that is, venous thromboembolism), arterial thrombotic stroke, and myocardial infarction. Sudden death attributable to any of these outcomes was included. The initial protocol was published before the studies began, and revisions to the protocol were also published.[viii,ix] The field work was done in 16 centres in five countries (Austria, France, Germany, Switzerland, and the United Kingdom). Field work is continuing in 10 centres.
The required ratio of three controls per case included at least one community control and one hospital control. We originally planned to have a minimum of four controls per case, but examination of the distribution of variables among controls in early 1994 showed that we could attain adequate statistical power with three controls. We did not use enrolled cases for whom we failed to match at least one control from the community and one from hospital. The British community controls were recruited from the same group general practice as the corresponding case (not necessarily the same general practitioner). In Germany population lists from the same neighbourhood were used. In France the matching method was similar to that in the United Kingdom, while in Switzerland and Austria the matching was based on neighbourhood population lists. The age range for both cases and controls was 16-44 years, with cases and controls matched for age within five year age bands. The other inclusion and exclusion criteria for both cases and controls are published separately.[vii-ix]
SUBJECTS
Enrolment of cases was concurrent, defined as within four months of the venous thromboembolism event or its diagnosis. All cases were identified in hospital. In addition, the appropriate authorities were contacted in order to identify all deaths diagnosed as due to venous thromboembolism that occurred in women aged 16-44 in the geographical area of the study. Diagnosis of deep vein thrombosis relied on pain and tenderness in the extremities, a precise record of knee circumference, and confirmation with imaging procedures. Diagnosis of pulmonary embolism was based on symptoms of pain in the chest or the side and confirmatory imaging procedures. Necropsy reports of the fatal events were reviewed. Log books of all cases enrolled and rejected were kept in all centres.
CONTRACEPTIVE USE
Current use of oral contraceptives was defined as use within the three months before the event (for a case), hospital admission (for a hospital control), or date of interview (for a community control). Only current use was considered to be a risk factor in the analyses; prior use was considered only for adjustment purposes
For the purpose of this analysis, we defined first generation oral contraceptives as any preparation that contained 50 micro g or more of ethinyloestradiol, regardless of progestogen content. Second generation oral contraceptives were defined as those containing 35 micro g or less of ethinyloestradiol and a progestogen other than gestodene or desogestrel. Preparations containing norgestimate were included with the second generation products, to retain consistency with the World Health Organisation analysis. There were 18 cases and 28 controls who used these products. Third generation oral contraceptives were defined as products contain ing low doses of ethinyloestradiol (usually micro g or 20 micro g) and either gestodene or desogestrel. Proges terone only pills containing no oestrogen were used by 17 cases and 34 controls. Precise definitions of the classifications of oral contraceptives are available from the authors.
INTERVIEWS
Interviews were conducted personally. We confirmed exposure to oral contraceptives by inspecting individual patients' packets of pills in samples of the cases and controls. Clinical data were verified with medical records when they were coded. All data were checked manually and by computer for eligibility and correct matching. We did double coding of clinical data and double entry with verification of all other data. Local and international panels of clinical specialists checked ail difficult or unreconciled diagnoses.
The original research questions for the case control study on venous thromboembolism were: (1) What is the relative risk of venous thromboembolism for current use of all oral contraceptives now on the market in the countries where the investigation was conducted, compared with no current use? (2) In the same countries what is the relative risk of venous thromboembolism for current use of low dose combinations of gestodene and ethinyloestradiol compared with all other low dose ethinyloestradiol oral contraceptives not containing gestodene or desogestrel?
In the light of the newly expressed concern about third generation products we added two other comparisons for analysis. (3) What is the relative risk of venous thromboembolism for current use of all third generation oral contraceptives compared with ail second generation products? (4) What is the relative risk of venous thromboembolism for current use of oral contraceptives containing desogestrel compared with all second generation products?
DATA ANALYSIS
After the quality assurance described above, we created a file of predetermined variables that we deemed essential or important: table 1 lists these "cardinal variables."
We used stratified analyses and unconditional logistic regression, with simultaneous adjustment performed with STATA 4.0 (Stata, College Station, TX, USA) were used to adjust for potential confounding variables (linear age, study centre, body mass index, smoking, alcohol use, and duration of use of oral contraceptives before the current exposure). Tables I and 2 show the categories in each variable. We did additional stratified analyses to search for unsuspected confounding variables and potential biases and also performed conditional logistic regression to assess whether overmatching had occurred.
| Table 1 - Cardinal variables used in logistic regression analysis | |
|---|---|
| Variable | Category |
| Major variables | |
| Age | In five year bands |
| Diagnosis for cases | As per protocol |
| Confidence of diagnosis | Possible, probable, certain |
| Diagnosis for controls | As per protocol |
| Area of residence | By centre and subcentre |
| Type of control | Community or hospital |
| Exposure to oral contraceptive | |
| User status | Never used, former user, current user |
| Type of contraceptive | Code |
| How recent the exposure | By month |
| Duration of exposure | By month |
| Potential confounders | |
| Life style: | |
| Smoking | Never, former, current |
| Alcohol consumption | No of drinks a day, a week, a month |
| Body mass index (kg/square metre) | less than 20, 20-30, 30 or greater |
| Medical history: | |
| Hypertension | Yes or no |
| Diabetes | Yes or no |
| Any pregnancies | Yes or no |
| Rheumatic heart disease | Yes or no |
| Family history: | |
| Stroke | Yes or no |
| Acute myocardial infarction | Yes or no |
| Educational status | Years of education |
| Table 2 - Distribution of selected variables from cardinal data set among study subjects in United Kingdom and Germany. Values are numbers (percentages) of subjects | |||
|---|---|---|---|
| Cases (n=471) | Hospital controls (n=789) | Community controls (n=983) | |
| Age group (years): | |||
| 16-24 | 133 (28.2) | 244 (30.9) | 255 (25.9) |
| 25-34 | 188 (38.4) | 310 (39.3) | 376 (38.3) |
| 35-44 | 157 (33.3) | 235 (29.6) | 352 (35.8) |
| Risk factors: | |||
| Body mass index 30 or over | 77(16.4) | 88(11.2) | 84(8.6) |
| Current smoker | 215 (45.7) | 346 (43.9) | 343 (34.9) |
| Alcohol intake (No of drinks): | |||
| more than 1 monthly and under weekly | 166 (35.2) | 285 (36.1) | 364(37.0) |
| under 1 weekly | 71(15.1) | 140 (17.7) | 218 (22.2) |
| Medical history: | |||
| Hypertension | 27 (5.7) | 36 (4.6) | 68 (6.9) |
| Diabetes | 11(2.3) | 13(1.7) | 8(0.8) |
| Pre-eclampsia | 22 (4.7) | 40 (5.1 ) | 37 (3.8) |
| Current use of oral contraceptive | 318 (67.5) | 329 (41.7) | 437 (44.5) |
| Year of accession: | |||
| 1993 | 71 (15.1) | 85 (10.8) | 108 (11.0) |
| 1994 | 286 (60.7) | 455 (57.7) | 599 (60.9) |
| 1995 | 114 (24.2) | 249(31.6) | 276 (28.1) |
For this report, we calculated adjusted odds ratios and their 95% confidence intervals to estimate the risk of venous thromboembolism associated with use of the various categories of oral contraceptives. To assist in the interpretation of the data and to examine how several possible biases might affect the estimates, we stratified by age and by first use of an oral contraceptive versus subsequent use. We also assessed how much the estimates were affected when controls were only from hospital or only from the community.
SOURCE OF DATA
This paper includes data primarily from the United Kingdom and Germany, where three years of field work have been completed, and is based on accrual of subjects up to 3 October 1995. At the time that this data set was created, field work had been in progress for less than one year in Austria, Switzerland, and France. Nevertheless, we also report the key odds ratios for all five nations combined.
The German data were affected by highly publicised regulatory actions taken by the Federal Institute for Drug Safety and Medical Products in 1989-90 with respect to a prominent third generation oral contraceptive, just as we were starting field work. This was reflected in low exposure rates to third generation products in our German data and thus very unstable point estimates. Accordingly, some analyses, mainly those relating to potential biases, were confined to the British data set. Similar analyses for Germany alone will be published in a German medical journal. We calculated aetiologic fractions separately for the United Kingdom and Germany by the method of Miettinen.[x] The fractions permitted calculation of rates of attributable deaths for each country based on national mortality registries. The total number of deaths occurring in each exposure category could then be determined by multiplying the overall total number of deaths by the proportion applying to that exposure category. The number of deaths in an exposure category with an odds ratio of OR1 that would be saved by switching to another category with an odds ratio of OR2 is:
(OR1-OR2)/OR1 x total number of deaths in the category to which OR1 applies"[xi,xii]
This last number is then summed across the six age groups to give the estimated total number of deaths that would be "saved" by switching. The calculation was for deaths from venous thromboembolism saved by switching from third generation oral contraceptives to second generation products. We based our calculations both on the Office of Population Censuses and Surveys' 1993 total of 103 deaths and on its 1992 total of 43 deaths.
For each exposure group (third generation, second generation, and first generation contraceptives and non-use), the proportion of total deaths in each age group is a function of the odds ratio for that exposure category and the prevalence of use for that exposure category.[xii] The estimates are based on the assumptions that (a) odds ratios from a study comprising mainly non-fatal cases can be generalised to fatal cases, (b) the odds ratios apply equally to all age groups, (c) assumption (a) applies equally to all age groups, and (d) the prevalence of use of the various oral contraceptive categories in the relevant population is reflected by the prevalence in the controls.
| Table 3 - Odds ratios of venous thromboembolism for current use of different groups of oral contraceptives | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| United Kingdom | Germany | Total | ||||||||
| Comparison | No of cases exposed (n=282) | No of controls exposed (n=1048) | Odds ratio (95% confidence interval)* | No of cases exposed (n=189) | No of controls exposed (n=724) | Odds ratio (95% confidence interval)* | No of cases exposed (n=471) | No of controls exposed (n=1048) | Odds ratio (95% confidence interval)* | |
| All oral contraceptives ** v no current use | 167 | 411 | 3.4(2.4 to 4.9) | 146 | 333 | 5.5(3.5 to 8.7) | 313 | 744 | 4.0 (3.1 to 5.3) | |
| First generation products*** v no current use | 1 | 3 | 2.0 (0.2 to 20.8) | 38 | 56 | 8.3 (4.5 to 15.2) | 37 | 59 | 5.7(3.4 to 9.4) | |
| Second generation products*** v no current use | 64 | 189 | 3.0 (1.9 to 4.5) | 68 | 213 | 3.7 (2.2 to 6.2) | 132 | 402 | 3.2 (2.3 to 4.3) | |
| Third generation products*** v no current use | 98 | 197 | 4.4 (3.0 to 6.6) | 29 | 52 | 6.7 (3.4 to 13.0) | 127 | 249 | 4.8 (3.4 to 6.7 | )|
| Products containing levonorgestrel v no current use | 37 | 131 | 2.5 (1.5 to 4.0) | 52 | 180 | 3.4 (2.0 to 5.7) | 89 | 311 | 3.0(2.0 to 3.9) | |
| Third generation products v second generation products*** | 98 | 197 | 1.5 (1.0 to 2.2) | 29 | 52 | 1.8 (1.0 to 3.3) | 127 | 249 | 1.5 (1.1 to 2.1) | |
| Products containing gestodene v second generation products*** | 45 | 101 | 1.4 (0.9 to 2.3) | 10 | 11 | 2.6 | (1.0 to 7.2) | 55 | 112 | 1.5 (1.0 to 2.2) |
| Products containing desogestrel v second generation products*** | 53 | 96 | 1.6 (1.0 to 2.5) | 12 | 25 | 1.5 (0.8 to 3.1) | 72 | 137 | 1.5 (1.1 to 2.2) | |
| *Adjusted for linear age, smoking, alcohol use, study
centre, body mass
index, and duration of exposure to oral contraceptives used before current oral
contraceptive.
**including progesterone only oral contraceptives. ***Users of progesterone only oral contraceptives (17 cases and 34 controls) were not classified as users of first, second, or third generation products. Thus rows and columns do not necessarily add up. Including them as third or second generation products makes no meaningful difference to odds ratios. |
||||||||||
We report results for 471 cases and 1,772 controls (789 from hospital and 983 from the community) in the United Kingdom and Germany (table 2). There were 183 cases of pulmonary embolism (with four fatal events) and 288 cases of deep vein thrombosis without report of pulmonary embolism.
Table 3 shows the key results. Overall, there was a fourfold higher relative risk of venous thromboembolism associated with current use of any oral contraceptive versus no current use. For any oral contraceptive, we included brands not fulfilling criteria for the three generations as defined. In the same comparison the odds ratio for the United Kingdom was 3.4 (2.4 to 4.9) and for Germany was 5.5 (3.5 to 8.7). For third generation contraceptives versus second generation products in both countries, the odds ratio was 1.5 (1.1 to 2.1). The odds ratios for second generation and third generation products versus no current use were 3.2 (2.3 to 4.3) and 4.8 (3. 4 to 6.7) respectively. Compared with no current use, the lowest point estimate we found for use of an oral contraceptive was for second genera tion products containing levonorgestrel. The odds ratios for third generation products containing gesto dene and for those containing desogestrel were similar. The point estimates for all comparisons were higher in the German data than the British data.
Table 4 shows the distribution of use of types of oral contraceptive by selected variables among 1,772 controls in the United Kingdom and Germany. These variables were the predefined subset of cardinal data, which are listed in table 1.
Results for all five countries - The odds ratio of venous thromboembolism associated with current use of any oral contraceptive versus no current was 4.5 (3.5 to 5.9), with 340 cases and 783 controls exposed to such products. For third generation products versus second generation products, the odds ratio was 1.7 (1.3 to 2.4), with 149 cases and 262 controls exposed. All other odds ratios were slightly higher than for the United Kingdom in Germany. The odds ratios for third generation products containing gestodene and for those containing desogestrel were similar, being 1.7 (1.2 to 2.5) and 1.8 (1.2 to 2.6) respectively.
| Table 4 - Distribution of use of oral contraceptives by selected variables from the cardinal data set among 1,772 controls in the United Kingdom and Germany. Values are numbers (percentages) of subjects | ||||
|---|---|---|---|---|
| Users of oral contraceptives* | ||||
| Non-users (n=1028) | 1st Generation (n=59) | 2nd Generation (n=402) | 3rd Generation (n=249) | |
| Age (years): | ||||
| 16-24 | 206 (20.0) | 1 1(18.6) | 147 (36.6) | 128 (51.4) |
| 25-34 | 372 (36.2) | 23 (39.0) | 177 (44.0) | 99 (39.8) |
| 35-44 | 450 (43.8) | 25 (42.4) | 78 (19.4) | 22 (8.8) |
| Body mass index 30 or greater | 127 (1.4) | 5 (8.5) | 26 (6.5) | 12 (4.8) |
| Alcohol intake (No of drinks): | ||||
| more than 1 monthly and under 1 weekly | 365 (35.5) | 11(18.6) | 160 (39.8) | 104 (41-8) |
| more than 1 weekly | 204 (19.8) | 11 (18.6) | 73 (18.2) | 62 (24.9) |
| Smoking | ||||
| Current smoker | 379 (36.9) | 28 (47.5) | 169 (42.0) | 97 (38.9) |
| Medical history: | ||||
| Hypertension | 71 (5.1) | 3 (5.1) | 18 (4.5) | 9 (3.6) |
| Diabetes | 16 (1.7) | 1 (1.7) | 1 (0.3) | 2 (0.8) |
| Pre-eclampsia | 57 (1.7) | 1(1.7) | 9 (2.2) | 4 (1.8) |
| Year of accession: | ||||
| 1993 | 111 (10.8) | 13 (22.0) | 50 (12.4) | 18 (7.2) |
| 1994 | 604 (58.8) | 32 (54.3) | 249 (61.9) | 147 (59.0) |
| 1995 | 313 (30.4) | 14 (23.7) | 103 (25.6) | 84 (33.7) |
| *Users of progesterone only pills (17 cases, 34 controls) not classified as users of first, second, or third generation oral contraceptives. | ||||
POTENTIAL BIAS
We considered a number of effects that might have biased our results, including differential prescription of the newer preparations and higher alertness leading to diagnostic or referral biases. To examine these possibilities we undertook additional analyses by diag nostic category and by whether women were using an oral contraceptive for the first time. The odds ratios of both categories of venous thromboembolism associated with use of third generation products versus use of second generation products were 2.0 (1.2 to 3.4) for pulmonary embolism and 1.2 (0.8 to 1.9) for deep vein thrombosis. In an analysis restricted to first time users of any oral contraceptive the odds ratio for use of third generation products versus second generation products was 2.7 (1.3 to 5.7); when the same analysis was restricted to women who had previously used an oral contraceptive the odds ratio was 1.4 (1.0 to 2.1).
The matched analysis (British and German data combined) for third generation versus second generation products resulted in an odds ratio of 1.6 (1.2 to 2.2). For second generation products versus no current use, it was 3.0 (2.2 to 4.0), and for third generation products versus no current use, it was 4 9 (3.6 to 6.7). When we compared third generation versus second generation products using community controls only, the odds ratio was 1.4 (1.0 to 2.0); with hospital controls only, it was 1.7 (1 2 to 2.5). For second generation products versus no current use, we found an odds ratio of 3-4 (2.4 to 4.9) with community controls and 3.5 (2.4 to 5.0) with hospital controls. For third generation products versus no current use, we found an odds ratio of 4.7 (3.3 to 6.8) with community controls and 6.0 (4.0 to 8.9) with hospital controls.
ESTIMATES FOR POPULATIONS
The population aetiological fraction for current use of all third generation oral contraceptives in comparison with use of second generation products was 9% in the United Kingdom and 11% in Germany. Given the prevalence of use of third and second generation preparations in the controls in this study and the observed odds ratio of 1.5 (1.1 to 2.1) for third compared with second generation products, the point estimate is consistent with an excess of five deaths based on the Office of Population Censuses and Surveys' 1992 total and 10 deaths based on the 1993 total. The confidence interval for the odds ratio and the change in coding of deaths from venous thromboembolism in England and Wales between 1992 and 1993 gives a range of one to 19 excess deaths from this cause per year. In Germany the range is from two to 15 additional deaths and the point estimate is consistent with seven excess deaths.
We have found a weak association, with an odds ratio of 1-5, between increased risk of venous thromboembolism and use of third generation oral contraceptives as opposed to second generation products. Before evaluating the clinical and public health significance of this observation, we must consider the effects of potential biases that might have distorted the risk estimates.
POTENTIAL BIAS
Diagnostic bias might have occurred if doctors had been more likely to investigate and hence to diagnose venous thromboembolism in women taking the newer oral contraceptives. However, the observed elevated odds ratio in cases with the more serious diagnosis of pulmonary embolism, which is likely to be investigated carefully in all women, militates against diagnostic bias.
Rx!ferral bias could have played a part if women receiving the newer oral contraceptives were more likely to be admitted to hospital. Almost all of our cases of venous thromboembolism were identified in hospitals. It is not possible to test for this bias in this data set.
Prescribing bias would have occurred if doctors had recommended newer products, advertised as safer, for patients with higher risk profiles. We adjusted for the presence of the risk factors for which we had data - that is, age, obesity and smoking - and found no change in our point estimates. We did not have any data on family history of venous thromboembolism. The existence of prescribing bias is not corroborated in our data.
A further potential bias might have occurred with attrition of susceptible subjects - meaning that the longer that one extends the window of observation, the fewer the adverse events noted per unit of time. That is because those patients susceptible to side effects tend to drop out of the corresponding user group at an early stage or are switched by their doctor to another product. In contrast, if a product is well tolerated prudent doctors and safety conscious patients tend to continue to use it, so that patients who will have been taking a product for a long time would be expected to be at lower risk than first time users of any brand.
If first time users of oral contraceptives were selectively prescribed preparations containing the newer progestogens a bias will have been introduced. First time users would include women at an unidentified higher risk of thrombosis due to genetic factors, while long term users are "survivors," who have remained free of events. Thus, our main reference group (second generation product users) may have comprised women at the lowest risk possible. When we adjusted for duration of lifetime use of oral contraceptives preceding the current use of oral contraceptive and for length of use of the most recent oral contraceptive, the point estimate did in fact decline by 12% to 1.4. We also confirmed that first time users were at appreciably higher risk than subsequent users. Also, as shown in table 3, users of second generation products containing levonorgestrel, which has been on the market for about 20 years, exhibited the lowest odds ratios we found when compared with no current use.
The matched conditional regression analyses strongly suggest that no overmatching occurred. Using community controls rather than hospital controls as reference groups made little difference in the estimates and in the resulting conclusions.
ASSESSMENT OF RISK
All the odds ratios reported are low, the point estimates ranging from 1.4 to 1.9 and the best adjusted estimate being 1.5. Venous thromboembolism is rare in young women, and the importance of the weak association observed in this study is better judged by the attributable risk. Given the prevalence of use of third generation oral contraceptives in the controls in this study, the observed odds ratio of 1.5 for preparations containing third generation as opposed to second generation progestogens might result in one to 19 excess deaths from venous thromboembolism annually in England and Wales. Given the various assumptions used in the calculations of deaths, we can only give a range of estimates for lives saved by switching from third generation oral contraceptives to second generation products.
Translating the results of epidemiological case-control studies to routine clinical practice is difficult, particularly when the associations found are not strong or are ambiguous. We have found a weak association between third generation oral contraceptives and venous thromboembolism when second generation oral contraceptives are the reference group. The modest increase in risk must be taken seriously even if it is not certain that the relation is causal. A woman using an oral contraceptive containing a third generation rather than a second generation progestogen may have an increased risk of death from venous thromboembolism of six per million per year in the United Kingdom. These excess events must be interpreted in the context of differences in mortality from myocardial infarction and stroke for users of oral contraceptives. The increased risk of venous thromboembolism alone is equivalent to the increased risk of death from cancer and heart disease if a woman smoked 10 cigarettes a year.[ii,vi] Our data justify clinical prudence but allow doctors and women seeking contraception to exercise informed choice.
Key messages
Concern has recently been raised that third generation oral contraceptives, which contain gonane progestogens (desogestrel, gestodene, and norgestimate), increase the risk of thromboembolism
This case-control study examined risk of venous thromboembolism associated with different types of oral contraceptive
Overall, there was a fourfold higher relative risk of thromboembolism associated with current use of any oral contraceptive versus no current use
The risk of thromboembolism was 1.5 times higher for third generation contraceptives compared with second generation products Our data indicate the need for clinical prudence but allow doctors and women seeking contraception to exercise informed choice
| Table A1 Distribution of selected cardinal variables among study subjects of all five countries. Values are numbers (percentages) of subjects | ||||||
|---|---|---|---|---|---|---|
| Cases (n = 501) |
Hospital controls (n = 828) | Community controls (n = 1040) | ||||
| Age groups: | ||||||
| 16-24 | 141 (28.2) | 253 (30.6) | 271 (26.1) | |||
| 25-34 | 195 (38.9) | 329 (39.7) | 403 (38.8) | |||
| 35-44 | 165 (32.9) | 246 (29.2) | 366 (35.2) | |||
| Risk factors: | ||||||
| Body mass index (kg/square metre): | ||||||
| less than 20 | 83 (18.6) | 172 (20.8) | 192 (18.5) | |||
| 20-29 | 337 (67.3) | 564 (68.1) | 762 (73.3) | |||
| at least 30 | 81 (16.1) | 92 (11.1) | 86 (8.3) | |||
| Smoking status: | ||||||
| Never | 204 (40.7) | 363 (43.8) | 515 (49.5) | |||
| Former | 68 (13.6) | 100 (12.1) | 165 (15.9) | |||
| Current | 229 (45.7) | 365 (44.1) | 360 (34.6) | |||
| Alcohol intake (no of drinks): | ||||||
| None | 79 (15.8) | 95 (11.5) | 78 (7.5) | |||
| less than 1 monthly | 172 (34.3) | 284 (34.3) | 346 (33.3) | |||
| greater than 1 monthly and less than 1 weekly | 176 (35.1) | 301 (36.4) | 387 (37.2) | |||
| greater than 1 weekly | 74 (14.8) | 148 (17.8) | 229 (22.0) | |||
| Parity: | ||||||
| No | 171 (34.1) | 313 (37.8) | 343 (33.0) | |||
| Yes | 330 (65.9) | 515 (62.2) | 697 (67.0) | |||
| Education: | ||||||
| equal to or below 10 years | 133 (26.5) | 196 (23.7) | 241 (23.2) | |||
| over 10 years | 330 (65.9) | 553 (66.8) | 684 (65.8) | |||
| University | 38 (7.6) | 79 (9.5) | 115 (11.0) | |||
| Medical History: | ||||||
| Hypertension | 31 (6.2) | 38 (4.6) | 71 (6.8) | |||
| Diabetes | 11 (2.2) | 14 (1.7) | 8 (0.8) | |||
| Rheumatic heart disease | 2 (0.4) | 0 | 1 (0.1) | |||
| Pre-eclampsia | 22 (4.4) | 40 (4.8) | 38 (3.7) | |||
| Use of oral contraceptives: | ||||||
| Never | 40 (8.0) | 130 (15.7) | 118 (11.4) | |||
| Former | 116 (23.1) | 356 (43.0) | 359 (44.1) | |||
| Current | 345 (68.9) | 342 (41.3) | 463 (44.5) | |||
| Year of accession: | ||||||
| 1993 | 71 (14.2) | 85 (10.3) | 108 (10.4) | |||
| 1994 | 295 (58.9) | 463 (55.9) | 661 (58.7) | |||
| 1995 | 135 (26.9) | 280 (33.8) | 321 (30.9) | |||
| Table A2 Abbreviated classification list of oral contraceptives included in study with major ingredients listed (full classification list available from authors) | ||||
|---|---|---|---|---|
| Oestrogen content | Other substance | Trade name | ||
| United Kingdom | Germany | |||
| First generation oral contraceptives* | ||||
| Ethinyloestradiol 50 micro g | Certostat | |||
| Ethinyloestradiol 50 micro g | Levonorgestrel | Ovran | Gravistat | |
| Ethinyloestradiol 50 micro g | Chlorrmadionone acetate | Neo-Eunomin | ||
| Ethinyloestradiol 50 micro g | Norethisterone acetate | Non-Ovlon | ||
| Ethinyloestradiol 50 micro g | Lynestrinol | Anacyclin | ||
| Ethinyloestradiol 50 micro g | Desogestrel | Oviol 22 | ||
| Ethinyloestradiol 50 micro g | Norgestrel | Eugynon | ||
| Second generation oral contraceptives+ | ||||
| Ethinyloestradiol 35 micro g | Norgestimate | Cilest | Cilest | |
| Ethinyloestradiol 30 micro g | Norethisterone | Ovysmen | Conceplan | |
| Ethinyloestradiol 35 micro g | Cyproterone acetate | Diane | ||
| Ethinyloestradiol 30 micro g | Norethisterone acetate | Loestrin 30 | ||
| Ethinyloestradiol 30 micro g | Levonorgestrel | Microgynon 21 | Microgynon 21 | |
| Ethinyloestradiol 30 micro g | Ethynodiole diacetate | Conova 30 | ||
| Ethinyloestradiol 37.5 micro g | Lynestrenol | Ovoresta M | ||
| Third generation oral contraceptives** | ||||
| Ethinyloestradiol 30 micro g | Gestodene | Femodene | Femovan | |
| Ethinyloestradiol 30 micro g | Gestodene | Minulet | Minulet | |
| Ethinyloestradiol 30 micro g | Desogestrel | Marvelon | Marvelon | |
| Ethinyloestradiol 20 micro g | Desogestrel | Mercilon | Lovelle | |
| * High dose oestrogen products with or without synthetic progestogen. | ||||
| + Low dose oestrogen ( 50 micro g) with progestogen other than gestodene or desogestrel. | ||||
| ** Low dose oestrogen with gestodene or desogestrel. | ||||
| Table A4 -- Definitions for cases | ||
|---|---|---|
| Group | ICD-9 (international classification of diseases, ninth edition) | |
| Code | Definition | |
| Acute myocardial infarction | 410 | Defined according to World Health Organisation criteria of chest pain, raised enzyme activity, and electrocardiographic results |
| Intracranial thromboembolism (includes the terms cerebrovascular accident and stroke; all definite haemorrhagic incidents excluded) | 362.3 | Retinal vascular occlusion |
| 433 | Occlusion and stenosis of precerebral arteries | |
| 434.0 | Cerebral thrombosis | |
| 434.1 | Cerebral embolism | |
| 434.9 | Occlusion of cerebral arteries, unspecified | |
| Pulmonary embolism and deep thrombosis of upper and lower extremities | 415.1 | Pulmonary embolism |
| 451.1 | Plebitis and thrombophlebitis of deep vessels of upper and lower extremities | |
Department of Epidemiology and Biostatistics McGill University Montreal CanadaWalter O Spitzer Strathcona professor of preventive medicine Michael A Lewis assistant professor
Centre for Epidemiology and Health Research Zepernick/Berlin Germany Lothar A J Heinemann director
London School of Hygiene and Tropical Medicine London Margaret Thorogood senior lecturer
Charing Cross and Westminster Medical School London Kenneth D MacRae reader in medical statistics
The investigators were accountable only to the scientific reference board (members listed below), which approved the protocol, received periodic reports, and conducted audits on the field and of the data before submission. This board was advised by the statistical advisory group (members listed below) on statistical issues. The board was also advised by an ad hoc peer review task force (members listed below). Data were processed in the Data Management Centre of the Potsdam Institute of Pharmacoepidemiology and Technology Assessment under the oversight of the statistical advisory group.
Funding: Unconditional grant from Schering AG Berlin.
Conflict of interest: Study was funded by Schering AG Berlin.
The Transnational Research Group on Oral Contraceptives and the health of Young Women consisted of:
Scientific Reference Board: U. Bergman, Karolinska I.; M. Breckwoldt, U. Freiburg; J. Collins, McMaster U.; F. Kemper, U. Munster; J. Le Lorier, U. of Montreal; S. MacLeod (Chair), McMaster U.; K. MacRae, Charing Cross and Westminster Medical School (until May 1995); W. Ray, Vanderbilt U. (since May 1995); J. Schlesselman, U. Pittsburgh.
Statistical Advisory Group: I. Guggenmoos-Holzmann, Freie U. Berlin; J. Hanley, McGill U.; M. Lewis, Potsdam Institute of Pharmacoepidemiology and Technology Assessment; K. MacRae, Charing Cross Hosp. and Westminster Med. Sch.; W. Ray, Vanderbilt U.; J. Schlesselman, Pittsburgh U.; S. Suissa, McGill U.
Ad hoc Peer Review Task Force: U. Bergmann, Karolinska I.; J. Daling, Fred Hutchinson Cancer Res. Ctre., U. Washington; M. Elstein, St. Mary's Hospital, Manchester; J. Hanley, McGill U.; S. Lock (Chair), Wellcome Trust; S. MacLeod, McMaster U.; W. Ray, Vanderbilt U.; L. Rosenberg, Boston U.; S. Suissa, McGill U.
British Steering Committee: V. Beral, Oxford U.; N. Cherry, Manchester U. (until June 1995); M. Elstein (Chair), St. Mary's Hospital, Manchester; M. Harrison, UCL Medical School; C. Kay, Royal Coll. of General Practitioners; M. Shipley, U. London.
German-Speaking Steering Committee: R. Brugger, AKS Bregenz; J.W. Dudenhausen, Freie U. Berlin; E. Fleck, German Heart Centre; I. Guggenmoos-Holzmann (Chair), Freie U. Berlin; U. Gundert-Remy, U. Gottingen; K. Kunze, Uniklinik Hamburg-Eppendorf; N. Victor, U. Heidelberg; C. Zippel, Klinik für innere Medizin und Rehabilitation, Berlin.
Senior Investigators: J.P. Boissel, Hopital Neuro-Cardiologique, Lyon; R. Bruppacher, U. Basel; L. Heinemann, Zentrum für Epidemiologie und Gesundheitsforschung; M. Lewis, Potsdam Institute of Pharmacoepidemiology and Technology Assessment; K. MacRae (Principal Medical Statistician), Charing Cross Hosp. and Westminster Med. Sch.; N. Poulter, UCL Medical School; W.O. Spitzer (Principal Investigator), McGill U.; M. Thorogood, London School of Hygiene and Tropical Medicine, U. London.
Centres: Austria: Bregenz: R. Brugger; H. Concin (Director); S.K. Fuchs; I. Michalek; C. Trotter. Graz: S. Hascher; S. Loibner; G. Stark (Director). Innsbruck: S. Alge; S. Hammerle: H. Jud; B. Kittinger; C. Pechlaner; K. Pfeiffer (Director), H. Ulmer. Salzburg: B. Gappmeyer; S. Humpeler; Weitgasser (Director); G. Scheurer. France: Bordeaux: H. Barlet; M. Baumevieille; B. Begaud (Director); A. Chaslerie; F. Haramburu; F. Penouil. Lyon (national co-ordinating centre): B. Boissel (Director); C. Cornu; J. Gillet; A. Le Goff; B. Ravis; N. Strang. Germany: Berlin (national co-ordinating centre): W. Barth; H. Behr; L. Heinemann (Director); T. Leonhard; B. Lorenz; F. Masius; K.-H. Mauritz; S. Moehner; B. Sykura; C. Thiel; O.J. Titlbach; C. Toussaint. Halle: J. Busse; W. Fleig; J. Haerting (Director until July1994); M. Hagert; H. Klette; F. Lautenschlaeger (Director since July 1994); H. Liebal; H. Podhaisky; W. Teichmann; S. Zierz. Hamburg: A. Heinemann; U. Lockemann; K. Pueschel (Director). Jena: F. Hoffmann (Director); G. Grohmann; U. Merkel. Magdeburg: B. Bremer; D. Haase; W. Hellenbrand; C. Kalninsch; C.Listing; B.-P. Robra (Director); M. Schwarz. Nordhausen: M. Lustermann (Director). Schwerin: I. Schulzki (Director); H. Voigt. Zwickau: S. Boethig (Director); C. Lorenz. Switzerland: Zurich: B. Candinas; F. Gutzwiller (Director); U. Kaser; N. Pua; J. Schilling. United Kingdom: Glasgow: L. de Caestecker (Director); E. Hamilton; S. Mitchell; M. Soler-Lopez. London (national co-ordinating centre): D. Curle; J Gibbs; H. Hemingway; G. Mein; M. Thorogood; N. Poulter; S. Smith. Manchester: P. Hannaford (Director since August 1995); Z. Evans; B. Faragher; S. Ferry; G. McHugh; C. McCollum (Director until August 1995); C. Sutcliffe. Southampton: A. Ascott; N. Dunn; R. Mann (Director); B. Weston.
Consultants: D. Liberthson (Technical Writing); Y. Lis, Carter-Lis Associates (Quality Assurance); M. Sands, Stanford U. (Bibliography); M.W.L. Davis, McGill U. (Quality Assurance).
REFERENCES
1 Vessey MP. Benefits and risks of combined oral contraceptives. Meth Inform Med 1993; 32: 222-4.
2 Stadel BV. Oral contraceptives and cardiovascular disease. NEJM 1981; 305: (Parts 1 and 2) 612-18 and 672-677.
3 Goldzieher JW. Advances in oral contraception. An international review of levonorgestrel and ethinyl estradiol. J Reprod Med 1983; 28 (1Suppl): 53-6.
4 Thorogood M. Oral contraceptives and cardiovascular disease: An epidemiologic overview. Pharmacoepidemiol Drug Saf 1993; 2: 3-16.
5 Kuhl H, Jung-Hoffman C, Heidt F. Alterations in the serum levels of gestodene and SHBG during 12 cycles of treatment with 30 micrograms ethinylestradiol and 75 micrograms gestodene. Contraception, 1988; 38: 477-86.
6 Jung-Hoffman C, Kuhl H. Interaction with the pharmacokinetics of ethinylestradiol and progestogens contained in OCs. Contraception, 1989; 40: 299-312.
7 Poulter N et al. A multinational case-contral study of cardiovascular disease and steroid hormone contraceptives. In press. J Clin Epid
8 Spitzer WO, Thorogood M, Heinemann L. Trinational case control study of OCs and health. Pharmacoepidemiol Drug Saf 1993; 2: 21-31.
9 Lewis MA, Assmann A, Heinemann L, Spitzer, WO. Transnational case- control study of oral contraceptives and health. Approved protocol revisions through September 1995. In press: Pharmacoepidemiol Drug Saf
10 Miettinen OS. Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol. 1974; 99: 325-332.
11 Cole, P. and MacMahon, B. Attributable risk percent in case-control studies. Br. J. Prev. Soc. Med., 1971; 25: 242-244.t
12 Levin, M.L. The occurrence of lung cancer in man. Acta Unio Int. Cancer, 1953; 9: 531-541.
13 Royal College of General Practitioners. Further analysis of mortality in oral contraceptive users. Lancet 1981; i: 541-546.
14 Vessey M.P. et al. Mortality in oral contraceptive users. Lancet 7 March 1981; 549-550.
15 Inman WHW, Vessey MP. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of child- bearing age. BMJ 1968; 2: 193-9.
16 Vessey MP, Doll R. Investigation of relation between use of OCs and thromboembolic disease. BMJ 1968; 2:199-205.
17 Ritchie LD, Berkeley MIK. Response of patients and doctors to the 1983 "Pill scare". J R Coll Gen Pract 1984; 34: 600-2.
18 Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of OCs: Possible modifying effect of formulation and age at use. Lancet 1983; 2: 926-30.
19 Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: A possible adverse effect of the pill. Lancet 1983; 2: 930-4.
20 Letters to the Editor. Oral contraceptives and cancer. Lancet 1983; 2: 1018-20.
21 Mihill C. Doctors and producers dispute risks of pill but users must weigh the odds. The Guardian October 20, 1995.
22 Vessey MP. Oral contraception and cancer. In: Filshie M, Guillebaud J. eds. Contraception: Science and Practice. London: Butterworths, 1989; 52-68.
23 Armstrong B, Stevens N, Doll R. Retrospective study of the association between use of rauwolfia derivatives and breast cancer in English women. Lancet 1974; 2: 672-5.
24 Heinonen OP, Shapiro S, Tuominen L, Turunen MI. Reserpine use in relation to breast cancer. Lancet 1974; 2: 675-7.
25 Boston Collaborative Drug Surveillance Program. Reserpine and breast cancer. Lancet 1974; 2: 669-671.
26 Wilson R. Analysing the daily risks of life. Technology Review 1979. 81 (4): 40-46.
Michael A Lewis, Walter O Spitzer, Lothar A J Heinemann, Kenneth D MacRae, Rudolf Bruppacher, Margaret Thorogood on behalf of Transnational Research Group on Oral Contraceptives and the Health of Young Women
Abstract
Objective - To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of myocardial infarction.
Design - Matched case-control study.
Setting - 16 centres in Austria, France, Germany, Switzerland, and the United Kingdom.
Subjects - Cases were 153 women aged 16-44 with a myocardial infarction event. Controls were 498 women (at least 3 controls per case) unaffected by myocardial infarction who were matched with their corresponding case for age and for hospital or community setting within four months of the index infarction.
Main outcome measures - Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables.
Results - The estimated odds ratio for myocardial infarction of third compared with second generation oral contraceptives among all 651 study subjects was 0.36 (95% confidence interval 0.1 to 1.2) (P equals 0.11). The odds ratio for the United Kingdom and Germany alone was 0.45 (0.1 to 1.8) (P equals 0.26). Other odds ratios for the five countries were 3.1 (1.5 to 6.3) (P equals 0.003) for use of second generation products v no current use and 1.1 (0.4 to 3.4) (P equals 0.9) for use of, third generation products v no current use. Among the confounding variables the independent contribution of smoking (for which adjustment was made in the above estimates) proved to be important (10.1 (5.7 to 17.9), P greater than 0 001).
Conclusion - An odds ratio of 0.45 with wide confidence intervals shows that third generation oral contraceptives compared with second generation products are associated with a reduced risk of myocardial infarction or with no difference. This finding from an interim analysis should be interpreted with extreme caution. However, the excess risk of venous thromboembolism associated with the use of third generation products may be balanced by the reduced risk of myocardial infarction associated with the same products.
Introduction
The aim of the transnational project was to examine the safety of the third generation combined oral contraceptives, which contain the progestogens gestodene and desogestrel. At the outset gestodene was of special interest because of concerns in the European regulatory agencies and prominent discussion in the medical and lay press. The project incorporated three matched case-control studies with virtually identical methods [i,ii] for which the exposure factor of particular interest was use of third generation oral contraceptives. The outcomes for the three studies were venous thromboembolism, myocardial infarction, and ischaemic (thrombotic) stroke. Results of the study testing an association between the third generation products and venous thromboembolism are reported in the accompanying article.[iii] We report here the initial results of the case-control study assessing and contrasting the relation between second and third generation oral contraceptives and myocardial infarction in young women. Case recruitment continues. Identification and quantification of publicity bias will be incorporated in an amended protocol if extended field work proves feasible in the United Kingdom.
Subjects and methods
The subjects were women aged 16-45 who were recruited in 16 centres in five countries (Austria, France, Germany, Switzerland, and the United Kingdom). In this paper we include results for all five countries as well as for the United Kingdom and Germany alone to permit concurrent evaluation of our results on venous thromboembolism and myocardial infarction. An average of three controls was matched to each case; at least one control was from a hospital and at least one from the community. We matched for age in five year age bands. The cases of myocardial infarction (International Classification of Diseases code 410) met the criteria of the World Health Organisation.[iv] Controls were identified and interviewed within four months of the myocardial infarction of the index case. Current use of oral contraceptives was defined as use within three months before the event for a case, the date of admission for a hospital control, and the date of interview for a community control. The field work, beginning with feasibility and pilot projects, started in July 1991, and case recruitment continued until November 1995. Recruitment of controls for this report continued until 15 November 1995.
We assessed current use of third generation oral contraceptives containing low doses of ethinyl oestradiol (usually 30 mug or 20 mu g) and one of two progestogens, gestodene or desogestrel. Second generation oral contraceptives (the main reference group) are other low dose ethinyl oestradiol preparations (under 50 mu g) with progestogens introduced to the market earlier. We report unmatched odds ratios with 95% confidence intervals and their P values. We combined community controls and hospital controls as our main reference group. Odds ratios were calculated by unconditional logistic regression to adjust for the potential confounders listed in the footnote to the table, of which current smoking was deemed to be the most important. We estimated the effect of smoking adjusted for use of oral contraceptives. Matched analyses were done as a sensitivity check and to determine whether overmatching may have occurred. Further details on methods have been published[i,ii] or are available from us. We used a general plan and operational procedures virtually identical with those of the WHO's study group[iv] on oral contraceptives to facilitate comparison of the results of that project with those of the transnational project.
We have outlined the method we used to calculate the number of lives "saved" by switching from second to third generation oral contraceptives in the accompanying paper.[iii]
| Table 1 -Odds ratios* for risk of myocardial infarction for current use of different types of oral contraceptives: principal results of transnational study | |||
|---|---|---|---|
| Comparison All cases (n = 153) All controls (n=498) | Odds ratio (95% confidence interval) | P value | No exposed controls |
| Third generation v second generation products | 0.36(0.1 to 1.2) | 0.1 | 6;34 |
| Third generation products v no current use | 1.1(0.4 to 3.4) | 0.9 | 6;34 |
| Second generation products v no current use | 3.1(1.5 to 6.3) | 0.003 | 23;45 |
| Hospital controls (n=210) | |||
| Third generation v second generation products | 0.91(0.2 to 4.6) | 0.9 | 6;11 |
| Third generation products v no current use | 1.9(0.4 to 8.7) | 0.4 | 6;11 |
| Second generation products v no current use | 2.0(0.8 to 4.9) | 0.1 | 23;26 |
| Community controls (n=288) | |||
| Third generation v second generation products | 0.25 (0.1 to 1.0) | 0.05 | 6; 23 |
| Third generation products v no current use | 0.9 (0.3 to 3.0) | 0.8 | 6;23 |
| Second generation products v no current use | 3.5(1.5 to 8.6) | 0.005 | 23;19 |
| *Adjusted for centre, age, body mass index, smoking, alcohol intake, and duration of exposure to oral contraceptives before current contraceptive. | |||
Results
We enrolled 153 cases of myocardial infarction (11 of them fatal) and 498 controls. Eighty two cases were identified in the United Kingdom, 47 in Germany, five in Switzerland, six in Austria, and 13 in France. When we compared current use of third generation with current use of second generation products as risk factors for myocardial infarction in all 651 women the odds ratio was 0.36 (0.1 to 1.2) (P=0.1; table 1). When current use of third generation products was compared with no previous use of oral contraceptives the odds ratio was 0.3 (0.1 to 1.0) (P=0.06). When we excluded the three countries with small sample sizes (Austria, Switzerland, and France) the estimates and confidence intervals became 0.45 (0.1 to 1.8) (P=0.26) for use of third generation v second generation products; 1.0 (0.3 to 3.5) (P=0.96) for current use of third generation products v no current use of oral contraception; and 2.2 (1.0 to 5.0) (P=0.07) for current use of second generation products v no current use.
When we compared women who currently used third generation oral contraceptives with those who currently used second generation products we considered the controls as two groups matched for hospital or community. The odds ratio was 0.91 (0.2 to 4.7) (P=0.9) for cases and hospital controls and 0.25 (0.06 to 1.0) (P=0.05) for cases and community controls.
In matched analyses the odds ratio was 0.40 (0.1 to 1.6) (P=0.19) in the comparison of third v second generation oral contraceptives. The odds ratio for second generation products v no use, was 3.1 (1.4 to 6.8) (P=0.01) and for third generation products v no current use 1.2 (0.34 to 4.4) (P=0.76). When current smoking was adjusted for use of oral contraceptives the odds ratio for the risk of myocardial infarction was 10.1 (5.7 to 17.9) (P less than 0.001) among our study subjects. Among women who used third generation products the crude odds ratio for current smoking was 3.1 (0.5 to 19.8) (P=0.23). Among those who used second generation products it was 11.1 (3.0 to 40.2) (P less than 0 001), and for women who were not current users of oral contraceptives the equivalent risk estimate was 7.7 (4.0 to 14.7)(P less than 0.001).
Given the prevalence of use of third and second generation preparations in the controls of this study, the observed odds ratio of 0.36 (0.1 to 1.2) for third compared with second generation products is consistent with a switch from second to third generation oral contraceptives, resulting in 12 fewer deaths from acute myocardial infarction per year in England and Wales. The confidence interval for the number of deaths gives a range from 18 fewer to three more deaths from acute myocardial infarction per year in England and Wales. In Germany the range is from 65 fewer deaths to 14 more; the point estimate is consistent with 46 fewer deaths annually with a switch from second to third generation oral contraceptives.
Discussion
Odds ratios for the risk of myocardial infarction ranged from 0.30 to 0.45 when we compared third generation with second generation oral contraceptives. These results are based on only six cases of acute myocardial infarction and 34 controls exposed to third generation oral contraceptives and on 23 cases and 45 controls exposed to second generation products. This is reflected in the crude odds ratio for the individual study components, which ranged from 0.06 (0.01 to 0.76); for one case and six controls) in the southern region (Austria, France, Switzerland) to 1-07 (0.25 to 4.55); for four cases and 18 controls) in the United Kingdom, with Germany having intermediate values (0.18 (0.02 to 1.62); for one case and 10 controls) . The combined odds ratio for continental Europe was 0.15 (0.03 to 0.72); for two cases and 16 controls). The overall, fully adjusted odds ratio for all five countries was 0.36 (0.1 to 1.2). The point estimates are consistent with a benefit in the range of twofold to fourfold for those who use third generation rather than second generation oral contraceptives. This finding is from an interim analysis so should be interpreted with caution. If the findings are confirmed by subsequent work, it would translate into an important public health message. The excess risk of venous thromboembolism associated with the use of third generation oral contraceptives may be offset by the reduced risk of acute myocardial infarction when compared with second generation products.
As for the accompanying study, this study may be biased in terms of diagnosis, exposure selection, as well as attrition of susceptible subjects (a potential bias described in the accompanying article).[iii] Adjustment for duration of use of current oral contraceptives reduced the odds ratios further for the comparisons between third and second generation products. Matched analyses suggest strongly that overmatching did not occur. We showed that cigarette smoking was associated with a much higher risk of heart attack than the use of either generation of oral contraceptives.
These results are from only one study. Experimental, clinical, and laboratory studies both support and contradict the epidemiological findings.[viii, ix] They cannot and should not be invoked to indict second generation oral contraceptives. The benefits of the well established low dose second generation oral contraceptives clearly outweigh their risk, particularly in developed and developing countries where third generation preparations have not been approved or are not available. They have dropped to half or less of the odds ratios observed in the epidemiological studies of oral contraceptives in the mid-1970s.[x, xi] The accompanying paper shows that products containing levonorgestrel, in particular, had law. profiles of risk.[iii] The risks associated with pregnancy still heavily outweigh those associated with the use of any oral contraceptive. Women incur many risks, including smoking, with higher likelihood of harm than the probabilities of myocardial infarction associated with the use of oral contraceptives reported here.
Our findings on the potential benefits of third generation oral contraceptives with respect to the risk of myocardial infarction against the backdrop of potential harm with respect to risk of venous thromboembolism show that all known risks and benefits should be evaluated simultaneously when decisions about such products are taken. Both generations of oral contraceptives can be recommended on the basis of judicious clinical advice by the doctor and the informed choice of the woman using contraception.
Key messages
Department of Epidemiology and Biostatistics McGill University Montreal Canada Michael A Lewis assistant professor Walter O Spitzer Strathcona professor of preventive medicine
Centre for Epidemiology and Health Research Zepernick/Berlin Germany Lothar A J Heinemann director
Charing Cross and Westminster Medical School London Kenneth D MacRae reader in medical statistics
Potsdam Institute of Pharmacoepidemiology and Technology Assessment (PIPTA) Potsdam Germany Rudolph Bruppacher senior epidemiologist
London School of Hygiene and Tropical Medicine London Margaret Thorogood senior lecturer
Correspondence to: Professor W O Spitzer, Potsdam Institute of Pharmacoepidemiology and Technology Assessment (PIPTA), Otto Erich Strasse 7,14482 Potsdam, Germany.
The investigators were accountable only to the scientific reference board (members listed at the end of the accompanying paper), which approved the protocol, received periodic reports, and conducted audits on the field and of the data before submission. The board was also advised on statistical issues by the statistical advisory group (members listed in the accompanying paper).Funding: Unconditional grant from Schering AG Berlin.
Conflict of interest: Study was funded by Schering AG Berlin.
i. Spitzer WO, Thorogood M, Heinemann L Transnational case-control study of oral contraceptives and health Pharmacoepidemiol Drug Saf 1993;2:21-31.
ii. Lewis MA, Assmann A, Heinemann L, Spitzer WO. Transnational case control study of oral contraception and health. Approved protocol revisions through September 1995. Pharmacoepidemiol Drug Saf (in press).
iii. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M, MacRae KD Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study.BMJ 1996;312:53-8.
iv.Poulter N, et al A multinational case control study of cardiovascular disease and steroid hormone contraceptives. J Clin Epidemol (in press)
v Levin ML The occurrence of lung cancer in man. Acta Unio Int Cancer 1953;9:531-41.
vi. Cole P, MacMahon B. Attributable risk percent in case-control studies. Br J Prev Soc Med 1971;25:242-4.
vii. Miettinen OS. Proportion of disease caused or prevented by a given exposure, trait or intervention. Am.J Epidemiol 1974;99:325-32.
viii. KJaer A, Lebech A-M, Borrgaarrd B, Refn H, Pedersen LR, Schierup L et al Lipid metabolism and coagulation of two contraceptives: correlation to serum concentrations of levongestrel and gestodene. Contraception 1989; 40: 665-73
ix. Engel HJ, Engel K, Behnke K, Lichtlen P Angiographische Befunde nach Herzinfarkt junger Frauen die Rolle oraler Kontrazeptiva. Herz 1987;12 290-5 10
x.Thorogood M Oral contraceptive and cardiovascular disease an epidemiological overview.Pharmacoepidemiol Drug Saf 1993;2:21-31.
xi. Royal College of General Practitioners. Oral contraceptives and health. An interim report from the oral contraception study London; Pitman Medical, 1974
Jean-Claude Desenclos, Philippe Bouvet, Elisabeth Benz-Lemoine, Francine Grimont, Helene Desqueyroux, Isabelle Rebiere, Patrick A Grimont
Abstract
Objective - To assess the magnitude of a nationwide outbreak of infection with Salmonella enterica serotype paratyphi B and identify the vehicle and source of infection.
Design - case finding study of S paratyphi B infection between 15 August and 30 November 1993; a pair matched case-control study; an environmental investigation at a processing plant that produced a raw goats' milk cheese incriminated in the outbreak; phage typing and genotyping of food and human S paratyphi B isolates.
Setting - France, 15 August to 30 November 1993.
Subjects - 273 patients with S paratyphi B infection; 59 pairs of cases and controls matched for age, sex, and city of residence.
Main outcome measures - Numbers of cases and incidence rates by region of residence and age; matched odds ratios for dairy food preferences.
Results - Among the 273 cases there was one death; 203 (78/) strains belonged to phage type 1 var 3. The incidence of infection was greatest in the region where goats' milk cheese is commonly produced. Comparison of cases and controls showed a 12-fold greater risk of illness (95% confidence interval 1.6 to 92.3) from eating brand A unpasteurised goats' milk cheese. S paratyphi B isolates of phage type 1 var 3 were recovered from cheese A, goats' milk at the plant processing cheese A, and goats' milk supplied to the plant by a single farm. Genotypic IS 200 typing of food and human 1 var 3 phage type isolates showed a common IS 200 pattern.
Conclusion - This outbreak emphasises the potential health hazards of widely distributed unpasteurised milk products in France and the need for their close bacterial monitoring.
Reseau National de Sante Publique 94415 Saint Maurice Cedex France Jean-Claude Desenclos medical epidemiologist Helene Desqueyroux resident Isabelle Rebiere medical epidemiologist
Centre National de Reference des Salmonella-Shigella Institut Pasteur Paris Philippe Bouvet deputy director Patrick A Grimont director
Direction Departementale des Affaires Sanitaires et Sociales des Deux-Sevres Niort France Elisabeth Benz-Lemoine public health physician
Centre National de Reference de Typage Moleculaire Enterique lnstitut Pasteur Paris Francine Grimont deputy director
Correspondence to: Dr Desenclos.
Tess Harris, Trevor Silver, Elizabeth Rink, Sean Hilton
Abstract
Objective - To identify the nature and extent of any vocational training deficit within the London initiative zone and investigate the reasons.
Design - Collation of statistics and postal questionnaire surveys.
Setting - Thames regions inside and outside the London initiative zone.
Subjects - General practice registrars, trainers, principals from non-training practices, and vocational training course organisers.
Main outcome measures - Trends in numbers of general practice registrars, proportions of trainers, views on current vocational training in inner London.
Results - Numbers of general practice registrars fell significantly between 1988 and 1993 within the London initiative zone and in England overall. The number of registrars within the zone fell by more than in the rest of the Thames regions, where the decline was not statistically significant. A lower proportion of principals were approved as trainers within the zone than in the rest of the Thames regions and England overall. In their responses to the survey (88% of inner London registrars responded and 81% of outer Thames registrars) registrars suggested that improving remuneration and personal safety would make training in London more attractive. Trainers and non-trainers (response rates 89x/c and 66% respectively) also suggested increasing remuneration for trainers together with more protected time for training.
Conclusions - Less vocational training takes place within the London initiative zone than in the rest of the Thames regions and England overall, although there are discrepancies in official statistics. As well as specific recommendations for improving recruitment to vocational training in inner London, measures to tackle inner city deprivation should also remain high on the political agenda.
Division of General Practice and Primary Care St George's Hospital Medical School London SW17 0RE Tess Harris clinical lecturer in general practice Trevor Silver honorary senior lecturer in general practice Elizabeth Rink research manager Sean Hilton professor of general practice and primary care
Correspondence to: Dr Harris.