Oral contraceptives and cardiovascular outcomes: cause or bias?

The 1995-1996 "pill" scare, which suggested that third-generation oral contraceptives (OCs) were associated with a greater risk of venous thromboembolism (VTE) than second-generation OCs, had serious social and public health consequences, as women discontinued OCs, resulting in unwanted pregnancies and unnecessary abortions. This article uses the Bradford Hill criteria, for diagnosing causality from an observed association, to interpret evidence from recent studies as to whether there is any difference in the risk of VTE between third- and second-generation OCs. Bias and the influence of confounders have also been examined in relation to the difference in the risk of VTE between third- and second-generation OCs reported in the 1995-1996 studies. It is clear from the results of this analysis that none of the Bradford Hill criteria are fulfilled. Thus, a causal relationship cannot be inferred from the alleged association of third-generation OCs with VTE. Indeed, it would appear that the unavoidable bias in observational research is a more likely explanation for the apparent difference in the risk of VTE between third- and second-generation OCs in the 1995-1996 studies. Recent studies, which employed more appropriate controls for these biases showed no difference in the risk of VTE between third- and second-generation OCs. A Danish study (1994-1996) demonstrated a lower risk of thrombotic morbidity and mortality with third-generation OCs compared with second-generation OCs. In addition, the Transnational study has shown that third-generation OCs have a significantly lower relative risk (0.3 [0.1-0.9]) for acute myocardial infarction (MI) compared with second-generation products. In conclusion, there is no convincing evidence for a difference in the risk of stroke or VTE between third- and second-generation OCs. Moreover, third-generation OCs may be associated with a lower risk of MI than second-generation OCs.

Recurrent use of newer oral contraceptives and the risk of venous thromboembolism.

The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.

Are wireless phones safe? A review of the issue.

Most wireless phones and their corresponding base stations operate at a very low power output and in the radiofrequency range of 800 to 2000 Megahertz. Current international guidelines protect against thermal biological effects in terms of the local or whole-body specific absorption rate (SAR). Potential non-thermal bio-effects resulting from the use of wireless phones are not established and laboratory (i.e., in vitro, in vivo) studies have shown conflicting results. Epidemiological studies of potential human health effects are few but are expected to emerge in the near future. Challenges to epidemiological research include difficult exposure assessment, selection of appropriate controls, potential confounding bias, and validation of outcome. Scientists, community advocacy groups, and public health professionals must be equipped to critically analyze the emerging evidence within a benefit/risk assessment framework.

The differential risk of oral contraceptives: the impact of full exposure history.

Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives.

PIP: This transnational study examined the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (OCs). The study analyzed data on 502 women aged 16-44 years with VTE and 1864 controls from 10 centers in Germany and the UK from 1 January, 1993, to 20 October, 1995. Information on lifetime exposure history from all subjects was added to the data set used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17,622 continuous exposure episodes comprising 47914 person-years of observation, the adjusted hazard ratio of VTE for the comparison of current users of third-generation versus current users of second-generation combined OCs was 0.8 (0.5-1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1-2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the transnational study data show no evidence for an increased risk of VTE with third-generation compared with second-generation combined OCs.

The aftermath of a pill scare: regression to reassurance.

In October 1995, following confidential exchanges of findings among investigators in several epidemiological studies, the UK Medicines Control Agency sent a 'Dear Doctor' letter to all clinical practitioners in the country. The letter alerted them to the possibility of an excess risk of venous thromboembolism among women taking combined oral contraceptives (OC) with the 'newer' progestins, notably desogestrel and gestodene. The communication provoked a major pill scare, not just in the United Kingdom but in other countries. The preliminary and unpublished findings from the four initial 1995-96 studies reported odds ratios (OR) ranging from 1.5 to 23 in the point estimates. These are very low relative risks but were communicated in a way that the public perceived as a 'doubling of the risks'. In the 3 years since the pill scare, additional research has been done. First, deliberate and careful analysis of some of the studies and replication of others have shown that the epidemiological investigations were affected by unavoidable systematic error. Three types of bias were demonstrated empirically, namely, prescription bias, referral bias and healthy user effect or attrition of susceptibles. All those biases would tend to drive OR spuriously upwards. Additional epidemiological studies have progressively shown lower ORs, some of them under the threshold of 1.0, i.e. 'no association'. Two major consensus assessments, one carried out by a World Health Organization Scientific Group and another undertaken by the International Federation of Fertility Societies, both attach little importance to differences between older (second generation) combined OC and newer ones (third generation). This paper is a synthesis of all published evidence since October 1995, at the time of the pill scare and in the 3 years since. In conclusion, all combined oral contraceptive pills are equally safe.

Bias versus causality: interpreting recent evidence of oral contraceptive studies.

Late in 1995 and early 1996, 4 epidemiologic studies were published that resulted in a crude mean weighted relative risk of approximately 2 when third-generation oral contraceptives were compared with second-generation oral contraceptives as risk factors for venous thromboembolism. This article reviews empirical evidence on bias or systematic error that may have influenced the estimates of association. The Bradford-Hill criteria to distinguish causality from an observed association were used to consider whether third-generation oral contraceptives cause an apparent excess in the occurrence of venous thromboembolism. Bias is more likely than a causal relationship to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation oral contraceptives. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation products have not been detected. The clinical importance and the public health significance of any differences among the various products with respect to adverse cardiovascular outcomes are trivial and undetectable because of the extremely low incidence of those disorders among users of oral contraceptives. The oral contraceptive pill is 99.9% effective when used correctly. All oral contraceptives on the market are safe and getting safer.

PIP: Four epidemiologic studies published in 1995-96 reported a crude mean weighted relative risk for venous thromboembolism of approximately 2 when third-generation oral contraceptives (OCs) were compared with second-generation formulations. This paper considers empirical evidence of bias or systematic error that may have influenced the estimates of association. Specifically, it asks 1) whether an odds ratio of 2 for venous thromboembolism in users of third- compared with second-generation OCs is accurate or has been spuriously increased by bias and 2) whether causality can be assumed from the observed association reflected in a relative risk of 2. Bias--particularly healthy user, prescription, and referral bias--is more likely than a causal association to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation OCs. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation OCs have not been detected. Moreover, the clinical importance and public health significance of any differences between these OCs in terms of adverse cardiovascular outcomes are trivial because of the extremely low incidence of these disorders among OC users.

Thromboembolic stroke in young women. A European case-control study on oral contraceptives. Transnational Research Group on Oral Contraceptives and the Health of Young Women.

A matched case-control study was performed between 1993 and 1996 in 16 centers in the United Kingdom, Germany, France, Switzerland, and Austria. The objective was to determine the influence of oral contraceptives (OC), particularly those containing modern progestins, on the risk for ischemic stroke in women aged 16-44 years. A total of 220 women who had had an incident ischemic stroke and were compared with 775 control subjects who were unaffected by stroke. At least one hospital and one community control subject per patient was matched and interviewed with the corresponding patient for 5-year age band and for area of residence. Crude odds ratios (95% confidence intervals [CI]) for ischemic stroke were as follows. For current use of any OC versus no use 2.3 (1.7-3.2), the adjusted odds ratio (OR) 3.6 (2.4-5.4). The OC associated risk was higher for first generation than for second or third generation OC. The risk estimates for patients versus community control subjects were always lower than for hospital control subjects. No major regional difference of the risk estimates was found. Compared with nonusers of OC without hypertension, women with hypertension who used OC had an almost 10-fold increased risk. However, OC users who had had a blood pressure check before OC prescription had a lower risk than did those without such a check. Smoking > 10 cigarettes/day is associated with higher risk of stroke, particularly for OC users. No significant effect was found for duration of OC use. We conclude that although there is a small relative risk of occlusive stroke for healthy women currently using OC, the attributable risk is very small because the incidence in this age group is very low. The small increase in risk of OC use may be further reduced by preventive efforts for cardiovascular risk factors, particularly hypertension and smoking.

Balanced view of risks of oral contraceptives.

PIP: Available studies on the association between the use of combined oral contraceptives (OCs) and the risk of three serious side effects (myocardial infarction, ischemic and hemorrhagic stroke, and venous thromboembolism) were reviewed at a World Health Organization (WHO) scientific group meeting held in November 1997. The group's findings have been published in the November 28, 1997, issue of "WHO Weekly Epidemiological Record." Of concern to the author of this letter to the editor was the exclusion, with no clear criteria, of many lead investigators from closed sessions. Also notable was the tendency of the panel to downplay controversies about the differences between second- and third-generation OCs in the risk of venous thromboembolism. Moreover, the conclusions on myocardial infarction minimize the likely protective effect of third-generation compared with second-generation OCs. Finally, the summary report does not mention possible bias sources or clarify the lack of clinical and public health significance of odds ratios of 2.0 or less for adverse effects that are extremely rare. In the author's opinion, WHO should have given greater emphasis to the continually improving safety of OCs.^ieng

The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women.

The objective of this study was to assess the risk of myocardial infarction (MI) associated with the use of new and old combination oral contraceptives (OC). A matched case-control study in 16 centers in Germany, the United Kingdom, France, Austria, and Switzerland explored the association of current use of combination OC with the occurrence of MI. Our subjects were 182 women aged 16-44 years with MI; the controls were 635 women without MI (at least one hospital control and one community control per case) matched for 5-year age group and region. The main outcome measures were odds ratios comparing current use of a specific group of OC against current use of other groups or against no current use. The adjusted overall odds ratio (OR; 95% confidence intervals) for MI for second generation OC versus no current use was 2.35 (1.42 to 3.89) and 0.82 (0.29 to 2.31) for third generation OC (low dose ethinyl estradiol, gestodene, and desogestrel). A direct comparison of third generation users with second generation users yielded an OR of 0.28 (0.09 to 0.86). In subgroup analyses, the odds ratio for the UK alone was 1.25 (0.36 to 4.29), while for continental Europe it was 0.10 (0.02 to 0.48). For hospital controls, the risk estimated was 0.98 (0.22 to 4.44), and 0.18 (0.04 to 0.65) for community controls. The independent risk of MI among current smokers adjusted for OC use was 7.21 (4.58 to 11.36). Among users of third generation OC, the OR for current smokers was 3.75 (0.65 to 21.74) and among users of second generation it was 9.50 (2.93 to 30.96). A comparison of OC use in the UK for the time before and after regulatory action was taken in October 1995 shows that the likelihood of a control (last control accrued June 1996) being treated with second generation OC is seven times higher after 1 November 1995 than it was before. Third generation OC are the first to be associated with no excess risk of MI. A significantly lower risk of MI is found when comparing use of third generation OC with use of second generation OC. There seems to be an impressive amelioration of risk among smokers using newer OC. An impact of regulatory action in the UK was found in the OC use spectrum of controls.

PIP: The risk of myocardial infarction associated with use of second- and third-generation oral contraceptives (OCs) was investigated in a matched case-control study conducted at 16 centers in Germany, the UK, France, Austria, and Switzerland. 182 women 18-44 years old with myocardial infarction were matched for 5-year age group and region with 635 controls (at least 1 hospital control and 1 community control per case). 57 cases and 156 controls reported exposure to OCs, of whom 7 cases and 49 controls had taken third-generation formulations. The adjusted overall odds ratio (OR) for myocardial infarction was 2.35 (95% confidence interval [CI], 1.42-3.89) for second-generation OC use versus no use but only 0.82 (95% CI, 0.29-2.31) for third-generation OC use versus no use. A direct comparison of third-generation and second-generation OC users yielded an OR of 0.28 (95% CI, 0.09-0.86). 80% of cases, compared with 37% of controls, were current smokers. The independent risk of myocardial infarction among current smokers adjusted for OC use was 7.21 (95% CI, 4.58-11.36). The OR for current smokers was 3.75 (95% CI, 0.65-21.74) among users of third-generation OCs and 9.50 (95% CI, 2.93-30.96) among users of second-generation formulations. These Transnational Study findings indicate that third-generation formulations are the first OCs to be associated with no excess risk of myocardial infarction; moreover, they substantially reduce this risk among smokers. The reduced risk of myocardial infarction associated with OCs containing desogestrel and gestodene compared with levonorgestrel may reflect the failure of third-generation progestins to inhibit the estrogen-related increase in sex hormone binding globulin.

First-time use of newer oral contraceptives and the risk of venous thromboembolism.

Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third generation oral contraceptives than with second generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of oral contraceptive use particularly among first-time users, are inconsistent. We reanalyzed data from the Transnational case-control study to assess the risk of VTE associated with first-time use of oral contraceptives as a function of its duration of use. Over the period 1993 to 1995, 471 cases of venous thromboembolism were identified in Germany and the United Kingdom. For each case, up to four controls were obtained, for a total of 1772 controls. Data on oral contraceptive use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second or third generation agents, or never users of oral contraception. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of oral contraceptive use by logistic regression and quadratic spline models. We found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of oral contraceptive use is essentially identical for second and third generation pills relative to never users. This rate ratio increases to around 10 in the first year of use and decreases to around two after 2 years of use, remaining at this risk level thereafter for both second and third generation agents. We conclude that second and third generation agents are associated with identical risks of venous thromboembolism when they are prescribed to women who are using oral contraceptives for the first time ever.

PIP: Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third-generation oral contraceptives (OCs) than with second-generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of OC use, particularly among first-time users, are inconsistent. The authors reanalyzed data from the transnational case-control study to assess the risk of VTE associated with first-time use of OCs as a function of its duration of use. Over the period 1993-95, 471 cases of VTE were identified in Germany and the UK. For each case, up to 4 controls were obtained, for a total of 1772 controls. Data on OC use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second- or third-generation agents or never-users of OCs. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of OC use by logistic regression and quadratic spline models. The authors found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of OC use is essentially identical for second- and third-generation pills relative to never-users. This rate ratio increases to about 10 in the first year of use and decreases to about 2 after 2 years of use, remaining at this risk level thereafter for both second- and third-generation agents. The authors conclude that second- and third-generation agents are associated with identical risks of VTE when they are prescribed to women who are using OCs for the first time ever.

Case-control study of oral contraceptives and risk of thromboembolic stroke: results from International Study on Oral Contraceptives and Health of Young Women.

OBJECTIVE: To determine the influence of oral contraceptives (particularly those containing modern progestins) on the risk for ischaemic stroke in women aged 16-44 years. DESIGN: Matched case-control study. SETTING: 16 Centres in the United Kingdom, Germany, France, Switzerland, and Austria. SUBJECTS: Cases were 220 women aged 16-44 who had an incident ischaemic stroke. Controls were 775 women (at least one hospital and one community control per case) unaffected by stroke who were matched with the corresponding case for 5 year age band and for hospital or community setting. Information on exposure and confounding variables were collected in a face to face interview. MAIN OUTCOME MEASURES: Odds ratios derived with stratified analysis and unconditional logistic regression to adjust for potential confounding. RESULTS: Adjusted odds ratios (95% confidence intervals) for ischaemic stroke (unmatched analysis) were 4.4 (2.0 to 9.9), 3.4 (2.1 to 5.5), and 3.9 (2.3 to 6.6) for current use of first, second, and third generation oral contraceptives, respectively. The risk ratio for third versus second generation was 1.1 (0.7 to 2.0) and was similar in the United Kingdom and other European countries. The risk estimates were lower if blood pressure was checked before prescription. CONCLUSION: Although there is a small relative risk of occlusive stroke for women of reproductive age who currently use oral contraceptives, the attributable risk is very small because the incidence in this age range is very low. There is no difference between the risk of oral contraceptives of the third and second generation; only first generation oral contraceptives seem to be associated with a higher risk. This small increase in risk may be further reduced by efforts to control cardiovascular risk factors, particularly high blood pressure.

PIP: A matched case-control study conducted at 16 centers in the UK, Germany, France, Switzerland, and Austria in 1993-96 investigated the influence of combined oral contraceptives (OCs) on ischemic stroke risk in women 16-44 years of age. Enrolled were 220 women who experienced an incident ischemic stroke and 775 controls matched on age, hospital, and community. The adjusted odds ratios for current use of first-, second-, and third-generation OCs were 4.4 (95% confidence interval (CI), 2.0-9.9), 3.4 (95% CI, 2.1-5.5), and 3.9 (95% CI, 2.3-6.6), respectively. High-dose estrogen OCs were associated with a greater ischemic stroke risk, regardless of the type of progestin. The risk ratio for third- vs. second-generation OCs was 1.1 (95% CI, 0.7-2.0). Compared with current non-users, the odds ratios for stroke were 4.5 (95% CI, 2.1-9.6) for second-generation OCs and 2.5 (95% CI, 1.4-4.4) for third-generation OCs. Risk estimates were lower if blood pressure had been screened before OCs were prescribed. Although these findings indicate current OC use--especially of first-generation formulations--is associated with a slightly increased risk of thromboembolic stroke, the absolute risk is very small in this age group and can be reduced by avoiding prescription of OCs to women with cardiovascular risk factors such as high blood pressure.