Use Of Third-generation Oral Contraceptives Research Articles

Abstracts to be presented at the 16th Meeting of the Japan Placenta Association 2008, 13-14 November 2008 Hamamatsu, Japan

Recently, observational studies have suggested an increased risk of nonfatal venous thromboembolic complications in women using oral contraceptives (OCs) containing the thirdgeneration progestins, gestodene and desogestrel. Because of the observational, rather than randomized, nature of these trials, the clinical relevance of these findings is difficult to interpret. Each study included one or more potential sources of bias. In particular, cases came almost exclusively from hospitalized patients with nonfatal venous thromboembo- lism, which represents only a minority of patients diagnosed with this condition according to current clinical practice. In the absence of a sound biologic rationale to explain the increased risk with third-generation OCs, and considering the potential sources of bias within the current studies, an alternative view argues against causality. Oral contraceptives remain safe and effective. Clearly, additional research is needed to determine the relationship between thromboembolic disease and the use of third-generation OCs. In the interim, women should be informed thoroughly with objective data on all risks associated with the use of OCs.

Markers for cardiovascular disease in monozygotic twins discordant for the use of third-generation oral contraceptives.

Oral contraceptives (OC) modulate the risk for developing cardiovascular (CV) diseases. The aim of this study was to determine whether the use of third-generation OC has an impact on markers of CV disease in genetically identical women. We performed an intrapair comparison in 27 monozygotic twin pairs, one of whom was taking third-generation OC, whereas the other was not using OC. Biometric parameters were ascertained and conventional and 24-h ambulatory blood pressure (BP) was recorded. A fasting blood sample was taken for the measurement of glucose, insulin, proinsulin, lipids, and insulin-like growth factor binding protein-1 (IGFBP-1). Insulin resistance and beta-cell function were calculated by homeostasis model assessment (HOMA). A 24-h urine sample for cortisol was obtained. Third-generation OC use increased 24-h ambulatory systolic and diastolic BP by 5.2 and 3.9 mmHg, respectively (both P=0.0003). There was no effect on glucose, insulin and proinsulin levels, and on HOMA parameters, but the IGFBP-1 levels were markedly raised (P=0.0009). The lipid profile showed a 34% increase in triglyceride levels (P < 0.0001), but also a 7% increase in HDL-cholesterol levels (P=0.037). Use of third-generation OC impacts on CV disease markers in young-adult genetically identical women. Some changes are beneficial (increased HDL-cholesterol), whereas others may be deleterious (increased BP and triglyceride levels) or have unknown effects at this time (increased IGFBP-1 levels).

Oral contraceptives and the risk of myocardial infarction.

An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations In a nationwide, population-based, case-control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.

Emerging evidence on oral contraceptives and arterial disease

A number of case-control studies published in recent years have shown an apparent increase in the risk of venous thromboembolism (VTE) associated with the use of third-generation oral contraceptives (OCs) compared with second-generation OCs. However, it is thought that these studies were subject to a number of biases that would have increased the risk estimates for third-generation OCs while lowering those for second-generation preparations. Data on the risk of ischemic stroke and myocardial infarction (MI) show no such difference between generations of OCs, with a statistically significant reduction in the risk of acute MI from first- to third-generation in one major study. Available results indicate that there is no significant increase in the risk of ischemic stroke or acute MI associated with the use of low-dose estrogen OCs in young women who are properly screened before use, and who have no pre-existing cardiovascular risk factors, such as smoking and hypertension, for these conditions. These findings should be taken into account when interpreting the results of studies on the risk of VTE in women taking combined OCs.

Third- and second-generation oral contraceptives are associated with similar risk estimates for venous thromboembolism

A scientific discussion between 1995 and 1999 addressed the question whether second- and third-generation oral contraceptives (OCs) were associated with different risks of venous thromboembolism (VTE). Results from three epidemiological studies became available in the course of 1995, in which such differences were observed. Although it was unclear at that time whether these observations reflected causality or were induced by bias and/or confounding, some regulatory bodies in Europe restricted the indication for use of third-generation oral contraceptives. Immediate media attention generated a pill scare in those, but also other, countries.Indications for the influence of bias were observed in the initial studies of 1995 and further substantiated in subsequent utilization and prescribing surveys. The most important bias seemed to be related to differences in age and duration of use between third- and second-generation OC users. A number of new studies as well as new analyses in two of the 1995 databases included measures to limit the effect of the identified biases/confounders. These studies observed similar risks of venous thromboembolism with second- and third-generation oral contraceptives. Two other recently published studies did not or could not include the same level of control for confounding and reported similar results as the 1995 studies, thus reconfirming the relevance of the identified confounders. Population data show that the massive switch in the UK from third-generation OCs to second-generation OCs in 1995 has not resulted in a reduction of the incidence of VTE in OC users after 1995, illustrating that the risk of VTE is not determined by the type of low-dose pill used. In addition, data from trend analyses, spontaneous reporting and studies addressing hemostatic mechanisms in pill-users also do not support a potential difference in risk of VTE between users of second- and third-generation OCs.

Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study

We have reported previously that, compared with use of second-generation oral contraceptives, the use of third-generation oral contraceptives is associated with increased resistance to the anticoagulant action of activated protein C (APC). Owing to the cross-sectional design of that study, these observations may have been subject to unknown bias or uncontrolled effects of the menstrual cycle. We aimed to overcome these sources of bias by doing a cycle-controlled randomised cross-over trial. The response to APC in plasma was assessed in 33 women who received two consecutive cycles of a second-generation oral contraceptive (150 microg levonorgestrel and 30 microg ethinyloestradiol) or a third-generation oral contraceptive (150 microg desogestrel and 30 microg ethinyloestradiol), and who switched preparations after two pill-free cycles. Normalised APC sensitivity ratios were calculated by measurement of the effect of APC on thrombin generation in the plasma of these women and in pooled plasma from 90 controls. Of the 33 women, five were excluded because not all required plasma samples were available. In the remaining 28 women, the normalised APC sensitivity ratio increased during treatment with both preparations. Compared with levonorgestrel, desogestrel-containing oral-contraceptive treatment caused a highly significant (p<0.0001) additional increase in normalised APC sensitivity ratio (0.51 [95% CI 0.37-0.66]). Normalised APC sensitivity ratios during oral-contraceptive treatment correlated with the values before oral-contraceptive use. Oral-contraceptive treatment diminishes the efficacy with which APC down-regulates in-vitro thrombin formation. This phenomenon, designated as acquired APC resistance, is more pronounced in women using desogestrel-containing oral contraceptives than in women using levonorgestrel-containing preparations. Whether acquired APC resistance induced by oral contraceptives explains the increased risk of venous thromboembolism in oral-contraceptive users remains to be established.

The changing scene--an unnecessary pill crisis.

A number of case-control studies published in 1995/1996 have shown an apparent increase in the risk of venous thromboembolism (VTE) associated with the use of third-generation oral contraceptives (OC). However, it was discussed very early on that these studies were subject to a number of biases or residual confounding that would have increased the risk estimates for third-generation OC while lowering those for second-generation preparations. Six new studies or analyses were performed trying to take into account many of the methodological problems that were discussed for the initial studies: Two population-based database analyses in the UK and Germany, a new analysis of the General Practice Registry database (GPRD) in the UK, an analysis of a new database of the Transnational study, a re-analysis of the original Transnational study with a new technique, and a population-based study in Denmark. These studies could not confirm a higher VTE risk in users of third-generation OC compared with those using second-generation OC. Data on the risk of arterial thromboembolism (ischaemic stroke and myocardial infarction) show no such difference between generations of OC, with a statistically significant reduction in the risk of acute myocardial infarction from first- to third-generation preparations in one major study. Some of the investigators concluded that there is very likely no increased risk of arterial thromboembolism associated with the use of low-dose oestrogen OC in young women who are properly screened for cardiovascular risk factors or for such conditions. These findings should be taken into account when interpreting the results of studies on the risk of VTE in women taking combined OC.

Three months use of third-generation oral contraceptives does not affect artery wall properties

In several studies, artery wall properties have been shown to differ between men and women. It has been hypothesized that these differences may result from hormonal influences but, in a previous study, we were unable to detect any influence of the menstrual cycle on artery wall properties. Therefore, we investigated the differences in artery wall properties, if any, between the menstrual cycle and the use of a third-generation oral contraceptive for 3 months. We investigated the right common carotid (CCA) and femoral (CFA) arteries of normotensive young (18–25-y-old) women volunteers ( n = 14). The arterial cross-sectional distensibility and compliance coefficients were determined by means of a specially designed ultrasonic wall-tracking device and automatic brachial artery cuff blood-pressure measurements. The menstrual cycles and the cycles during oral contraceptive use (30 μg ethinylestradiol and 75 μg gestodene) were monitored by ultrasonographic evaluation and the assessment of plasma levels of 17β-oestradiol and progesterone. The distensibility and cross-sectional compliance coefficients of both the CCA and CFA did not differ significantly between the menstrual cycle and the use of oral contraceptives, despite different ovarian hormone levels. Brachial arterial blood pressure was also not affected. We conclude that 3 months use of a third-generation oral contraceptive does not influence the wall properties of peripheral arteries and cannot explain the observed difference between genders. The absence of a rise in blood pressure and the low androgenic profile of this specific oral contraceptive may have contributed to our findings.

Combined oral contraceptives, smoking, and cardiovascular risk.

STUDY OBJECTIVE: To assess age specific incidence and mortality of stroke, acute myocardial infarction (AMI), and idiopathic venous thromboembolism (VTE) associated with use of modern low dose combined oral contraceptives...

Molecular biology and pathophysiology of APC resistance: current insights and clinical implications.

APC resistance is often associated with the occurrence of a single point mutation in factor V (factor VLeiden) at a predominant cleavage site for the natural anticoagulant, activated protein C (APC). In this article we will discuss the effects of this mutation (Arg506-->Gln) on the down-regulation of factor Va cofactor activity and on thrombin formation by APC in model systems and in plasma. Our studies on the effects of APC on thrombin formation in plasma resulted in the development of a new method for the screening of APC resistance that is based on measurement of the effect of APC on the endogenous thrombin potential (the time integral of thrombin generated in clotting plasma). It appeared that sensitivities for APC determined via this method were considerably affected by the use of oral contraceptives (OC) and that women who use OC become acquired APC resistant. The fact that acquired APC resistance in women who use third-generation OC was more pronounced than in users of second-generation OC may explain the further increased risk for venous thrombosis associated with the use of third-generation OC.

Oral contraceptives and thrombosis.

Recent studies have identified an increased risk of venous thromboembolism associated with use of third-generation oral contraceptives (OCs). Use of these newer formulations has been estimated to cause an excess of 10 deaths/year in the UK. The possibility has been raised, however, that prescribing bias and confounding by duration of OC use and other personal risk factors accounts for the difference in the risk of venous thromboembolism between second- and third-generation OCs. Other studies have identified an increased risk of myocardial infarction and stroke in OC users, including users of low-dose formulations, but this risk is almost exclusively limited to older women who smoke or have other cardiovascular risk factors. The interpretation of all such studies on OC side effects should take into account that the absolute risk of an adverse thrombotic event while taking OCs is small. This risk appears to be affected far more by factors such as smoking, age, hypertension, and familial disorders than the type of progestagen contained in the OC.

Combined oral contraception and the risk of venous thromboembolism.

The "pill scare" of 1995 (triggered by the recommendation of the UK Committee on Safety of Medicines that users of third-generation formulations switch to second-generation pills) created a need for re-education of both the medical profession and the general public about the risks and benefits of combined oral contraceptives (OCs). The 1995 announcement led to widespread confusion and mistrust, as well as discontinuation of all OC use on the part of many of the 1.5 million UK users of third-generation pills. An estimated 10,000 more induced abortions and 30,000 more conceptions than expected from previous patterns occurred in the 9 months following the Committee's announcement. Ironically, the risk of nonfatal venous thromboembolism associated with pregnancy is twice that associated with the use of third-generation OCs. Ways must be found to keep women, physicians, and other health care professionals informed about the latest research findings and their clinical implications without creating a recurrence of the 1995 panic. Research data should be presented in terms of both the absolute and relative risks, and drug safety issues should be debated among the experts before premature pronouncements are issued through the mass media.

Venous Thromboembolism And `Third-Generation' Pills May Not Be Related

A recently published case-control study conducted in the UK suggests that the association between venous thromboembolism risk and use of third-generation oral contraceptives (OCs) identified in an earlier cohort analysis may be an artifact of age confounding. The investigators used computerized records from 143 general practitioners in the UK to compare the incidence of venous thromboembolism among users of the most common OCs and they performed a case-control study to calculate the odds ratio associated with different types of pills. The final sample included 491908 women born during 1941-81 who contributed 234899 woman-years of exposure to steroidal contraception including 108824 woman-years of exposure to third-generation progestogens. In all 85 women had a history of venous thromboembolism (29 users of second-generation OCs 54 users of third-generation products and 2 users of progestin-only pills). After adjustment for 5-year age groups users of third-generation pills were 1.7 times more likely than users of second-generation OCs to have experienced venous thromboembolism a finding consistent with the results of previous studies. The case-control portion of the study compared the 83 women who had a venous thromboembolism with 313 controls matched by physicians practice current OC use and exact year of birth. Regression analyses adjusted for potentially confounding variables revealed no significant differences in venous thromboembolism risk between users of second- versus first-generation OCs. The investigators contend that matching by exact age not 5-year age bands is essential to ensure that controls are representative of the population from which cases are drawn.

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 with-out 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.

10 The pill and thrombosis: epidemiological considerations

The oral contraceptive is one of the most widely taken medications in the healthy population. The clinically important side-effects are venous and arterial thrombosis. Accurate estimates of incidence of these side-effects have proven to be difficult. Diagnostic modalities for thrombosis are sub-optimal and the problems of study methodology, primarily a reliance on non-experimental studies, have limited the ability to define the attributable risk of thrombosis from oral contraception. Pharmacological attempts to further decrease venous thrombotic side-effects by the use of third-generation oral contraceptives have failed. This places a greater emphasis on the selection of patients to help avoid giving medication to those patients with underlying thrombotic risk factors. An example of this approach has been the clear confirmation of the adverse effects of cigarette smoking and arterial thrombosis in oral contraceptive users. At the biochemical level, hypercoagulability testing may be useful. Screening for high-frequency prothrombotic abnormalities, such as the Factor V Leiden genotype, represents an important addition to the process by which patients are selected, and may be prototypic of further advances.

New Study Casts Doubt on the Association Between Third-Generation Pills and Venous Thromboembolism

A recent case-control study from the UK raises doubts about the previously noted association between venous thromboembolism and use of third-generation oral contraceptives (OCs) containing the progestins gestodene and desogestrel. The computer records of 143 general practitioners in the UK yielded data on 540000 women born from 1941 to 1981. This sample included 491908 women with 234899 woman-years of exposure to steroidal contraception including 108824 woman-years of exposure to third-generation OCs. 85 women had a venous thromboembolism (29 users of second-generation OCs 54 users of third-generation pills and 2 users of progestin-only pills). The crude rates of venous thromboembolism were 4.1/10000 woman-years of exposure among all combined OC users 3.1/10000 for second-generation OCs and 5.0/10000 for third-generation products. After adjustment for 5-year age groups users of third-generation OCs were 1.7 times more likely than second-generation pill users to have experienced this complication. Case-control analysis of the same data set produced substantially different results however. The 85 women with a venous thromboembolism were matched with 313 controls on physicians practice current use of OCs and exact date of birth. After adjustment for body mass index change in type of contraceptive prescribed within 3 months of the event number of cycles prescribed concurrent disease and use of emergency contraception there was no significant difference in risk of venous thromboembolism associated with second- versus third-generation OCs. Exact matching by age appears crucial to ensure that controls are representative of the population from which cases are drawn and to prevent residual confounding by age.

Third-generation oral contraceptives and thromboembolism risk

Recently, observational studies have suggested an increased risk of nonfatal venous thromboembolic complications in women using oral contraceptives (OCs) containing the third-generation progestins, gestodene and desogestrel. Because of the observational, rather than randomized, nature of these trials, the clinical relevance of these findings is difficult to interpret. Each study included one or more potential sources of bias. In particular, cases came almost exclusively from hospitalized patients with nonfatal venous thromboembolism, which represents only a minority of patients diagnosed with this condition according to current clinical practice. In the absence of a sound biologic rationale to explain the increased risk with third-generation OCs, and considering the potential sources of bias within the current studies, an alternative view argues against causality. Oral contraceptives remain safe and effective. Clearly, additional research is needed to determine the relationship between thromboembolic disease and the use of third-generation OCs. In the interim, women should be informed thoroughly with objective data on all risks associated with the use of OCs.

"Increased Number of Induced Abortions in Norway after Media Coverage of Adverse Vascular Events from the Use of Third-generation Oral Contraceptives."

Abstract After the press release in Lancet (October 18, 1995) of increased risks for adverse vascular events in users of pills containing desogestrel and gestodene, the total sales of oral contraceptives dropped over a two-month period by 17%, while sales of the only desogestrel brand available (Marvelon) dropped by over 70% in Norway. From sales, we can estimate that more than 45,000 women either changed from Marvelon to a second- or first-generation brand or stopped using OCs. In total, more than 25,000 women discontinued OC use in Norway during November and December of 1995. Abortion data from one Norwegian county, representing 6–7% of the Norwegian population, show no statistically significant changes in the total number of induced abortions from the first quarter of 1996 as compared with that of the first quarter in preceding years. However, abortion rates that had been steadily decreasing from 1992 through 1995 in women 24 years old or younger, were promptly interrupted by a significant 36% increase during the first quarter of 1996. Most of the additional cases were found among single, childless studients. The observed increased abortion rate among younger women is most probably linked to changes in contraceptive use during the pill scare of late October through December of 1995, during which time these women conceived.

Increased number of induced abortions in Norway after media coverage of adverse vascular events from the use of third-generation oral contraceptives

After the press release in Lancet (October 18, 1995) of increased risks for adverse vascular events in users of pills containing desogestrel and gestodene, the total sales of oral contraceptives dropped over a two-month period by 17%, while sales of the only desogestrel brand available (Marvelon) dropped by over 70% in Norway. From sales, we can estimate that more than 45,000 women either changed from Marvelon to a second- or first-generation brand or stopped using OCs. In total, more than 25,000 women discontinued OC use in Norway during November and December of 1995. Abortion data from one Norwegian county, representing 6–7% of the Norwegian population, show no statistically significant changes in the total number of induced abortions from the first quarter of 1996 as compared with that of the first quarter in preceding years. However, abortion rates that had been steadily decreasing from 1992 through 1995 in women 24 years old or younger, were promptly interrupted by a significant 36% increase during the first quarter of 1996. Most of the additional cases were found among single, childless studients. The observed increased abortion rate among younger women is most probably linked to changes in contraceptive use during the pill scare of late October through December of 1995, during which time these women conceived.

Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies

Recent epidemiological studies have reported an approximately two-fold, significant, increased odds ratio for venous thromboembolism in users of third-generation oral contraceptives (OCs) compared to users of second-generation OCs. However, in each study, this association is of borderline statistical significance, and the studies do not indicate an increase in the absolute risk of venous thromboembolism for users of third-generation OCs compared with the data from prior studies primarily involving second-generation products. The data derived from these recent studies show a lower reported incidence of venous thromboembolism with the use of second-generation OCs over time compared to the prior studies, while the incidence of venous thromboembolism for use of third-generation OCs is approximately equal to that previously reported for second-generation products. Generally, evidence has shown that the risk of venous thromboembolism and the impact on hemostatic parameters are reduced with declining estrogen dose. In addition, there is no evidence of a clinically significant effect of the OC progestogen doses on hemostatic parameters. These inconsistencies point to factors other than a causal relationship to explain the higher risk of venous thromboembolism in users of third-generation OCs. An examination of factors not included in the recent studies has identified at least three potential biases that should be considered: prescription bias, a 'healthy-user' effect and referral bias. Available data on prescription bias come from marketing research surveys, databases of prescribing patterns, epidemiological databases and the recent studies. These data indicate that the recently introduced third-generation OCs have been more extensively used by younger women, for shorter periods of time, and by women with risk factors for venous thromboembolism that have the second-generation OCs. There is also evidence for a healthy-user effect, whereby women who were most susceptible for venous thromboembolism have left the cohort of users of second-generation OCs as a result of a venous thromboembolism during pregnancy or early OC use, and thus were possibly not included in these recent studies. The women remaining in the cohort, who are included in the recent studies, are less susceptible to venous thromboembolic events than are those making up the cohort of women using third-generation OCs. In addition, there are indications that referral bias has occurred because women with risk factors for venous thromboembolism (who disproportionately receive third-generation OCs) are more likely to be referred to a hospital for investigation of possible symptoms of venous thromboembolism, and thus users of third-generation OCs have the potential to be over-represented among cases. These biases act spuriously to increase the observed odds ratio for the first-time occurrence of venous thromboembolism amongst users of third-generation OCs, when compared to users of second-generation OCs. None of the recent epidemiological studies have been able to adjust for the three major biases. These biases are likely to contribute to, or even totally account, for the small increased risk of venous thromboembolism observed for users of third-generation OCs when compared to that for users of second-generation OCs.