Sunday, April 30, 2006

Would You Be Comfortable Using NuvaRing, the Vaginal Ring?

Somewhat surprising news from a study looking at Nuva Ring user characteristics--you don't have to be all that comfortable with touching your genital area to be a satisfied NuvaRing user:

At least 30% of women starting a reversible contraceptive method discontinue use within 6 months, and many women have difficulty using pills consistently. New delivery systems, including the vaginal ring, may be easier to use than traditional oral contraceptives because they require no daily action from users. The vaginal contraceptive ring cycle consists of 3 weeks of continuous ring use followed by 1 ring-free week. In observed trials, the vaginal ring has an efficacy and an adverse-effect profile similar to those of oral contraceptives.

Women's experience with their bodies may affect acceptability, satisfaction and continuation of contraceptives in a complex way. This may be especially salient for use of the vaginal ring, which requires women to touch their genitals for insertion and removal. Thus, clinicians may not offer the vaginal ring as an option because they believe that their patients would be uncomfortable touching their genitals to insert and remove the ring.

Anticipated discomfort may impede willingness to use the vaginal ring. Data from the National Health and Social Life Survey (NHSLS), with a probability sample of 3432 Americans, indicate that 58% of women report never masturbating. The NHSLS also found that 14% of women reported experiencing pain during intercourse. Women who do not masturbate or who report painful intercourse may have more discomfort with genital touching and be less willing to use the ring. Recent use of vaginal contraceptives has been extremely low in the United States; in the 2002 National Survey of Family Growth, less than 1% of current contraceptive users reported using a diaphragm, cervical cap, female condom, sponge or any other vaginal contraceptive. This suggests that vaginal contraception may not be attractive to many American women. This may be due to vaginal contraceptives' lower efficacy and to some women's unwillingness to touch their genitals.

We carried out this study to identify factors associated with vaginal ring satisfaction and continuation. We hypothesized that women who reported greater comfort in touching their genitals, greater frequency of masturbation, more comfort with intercourse and past use of vaginal contraceptives and products would be more likely than others to be satisfied with the ring and continue using it for birth control.


And yet, when it comes to continued NuvaRing use, the study found that:

High user satisfaction and continuation of the vaginal ring for birth control were not associated with prior use of vaginal contraceptives or products, masturbation, discomfort with intercourse or other behaviors that involve genital touching such as waxing and shaving pubic hair or having tattoos and/or body piercings. Neither demographic characteristics nor vaginal experiences identified successful ring users.


Some limitations of the study:

In this study, we did not collect data regarding frequency of vaginal intercourse; therefore, we do not know if this factor is related to satisfaction with ring use. Our findings indicate that most women who are willing to try the vaginal ring as part of a clinical trial are likely to be highly satisfied with the method and to continue using it. Women willing to participate in a randomized clinical trial are not, however, representative of average ring users, so these findings may not be generalizable.

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Saturday, April 29, 2006

Surrogate Markers and Clinical Risks of Contraceptive Use

Another good article from Contraception: Is some of the information on contraceptive risks in the package inserts accurate and useful, or is it a barrage of innuendo and pseudo-science?

The development of safe and effective contraceptive options for women is the direct result of advances in laboratory-based research, which has provided an important foundation for the development of an evidence-based approach to contraceptive management. This marriage of laboratory and clinical investigation has not only served to better delineate pathophysiological processes but also has expanded our understanding of the mechanisms of therapeutic actions. However, when laboratory-based studies alone are used to explain clinical outcomes, prediction of clinical outcomes can be corrupted by a lack of clinical information and replaced by a process replete with unsupported assumptions, premature declarations and unfounded concern about the safety and effectiveness of therapeutic interventions. Such a disingenuous application of high-quality laboratory investigation is unfortunately now more commonly used to predict clinical risks of contraceptive use. In several instances, warnings and specific language have been included in the package inserts of contraceptives based on nonclinical studies.

Nonclinically based outcome variables, or surrogate markers, are studied to ostensibly better understand the pathophysiological basis of clinical outcomes associated with the use of particular drugs or therapeutic interventions. However, when such surrogate markers are studied to predict clinical outcomes in the absence of data assessing clinical outcomes, they may lead to unsubstantiated clinical predictions. An example of a surrogate marker and its inappropriate application for predicting clinical outcomes is the measurement of the size and number of ovarian follicles among users of oral contraceptive pills. Those pills associated with more numerous and larger ovarian follicles are "assumed" to be less potent and thus place a woman at a potential increased risk for pregnancy while using that pill. However, the presence or absence of follicles has never been actually correlated with contraceptive pill efficacy. Only a direct determination of pregnancy rates among users of specific contraceptive methods can provide meaningful information about the actual effectiveness of a given contraceptive.


Other examples of using surogate markers to predict risk:

Depo-Povera shot and the risk of bone fracture

In the past, the language of the package insert and all emboldened and boxed warnings communicated well-defined clinical risks, such as the increased risk of adverse cardiovascular events in women who smoke and use estrogen-containing oral contraceptives after the age of 35. Unfortunately, the language and warnings of package inserts have increasingly incorporated surrogate marker studies to arrive at pronouncements of clinical risk. For example, a black box warning in the package insert of Depo-Provera CI warns that the use of the product will diminish the calcium stored in bones and that this could cause an increased risk of fracture. Have studies consistently shown reduced bone mineral density among women using Depo-Provera CI? Yes, studies of a wide spectrum of women using Depo-Provera CI have consistently demonstrated reduced bone mineral densitometry measurements among Depo-Provera CI users. But has there been any study that has demonstrated an increased risk of fracture among any women (pre- or postmenopausal) using Depo-Provera CI? The answer is no. The measurement of bone mineral density in reproductive-age women is a surrogate marker with no known clinical relevance. Moreover, the suggestion that women should consider using an alternative method after 2 years of Depo-Provera CI use is not based on scientific or clinical evidence and may cause clinicians to inappropriately switch their patients to less effective contraceptives. Such changes will place women at increased risk for unintended pregnancy and induced abortion.

Finally, the language of the Depo-Provera package insert also suggests that clinicians "test the bones" of women who wish to continue this method for more than 2 years. As bone densitometry has been shown to be ineffective and inappropriate for assessing fracture risk in the vast majority of premenopausal women, what test is being suggested?


The Ortho Evra patch and the risk of serious adverse events

Unfortunately, this trend in drug warnings continues with the recently added language and new warnings incorporated into the package insert of the transdermal patch Ortho-Evra®. The new emboldened warning for Ortho-Evra is not based on studies of clinical outcomes, but rather nonclinical pharmacokinetic studies that have found that women who use the transdermal contraceptive patch have a greater overall exposure (approximately 60%) to ethinyl estradiol than those women who use a conventional oral contraceptive with 35 μg ethinyl estradiol. A recent study by van den Heuvel et al. compared the exposure to ethinyl estradiol among users of the transdermal patch, the vaginal ring (Nuva Ring) and an oral contraceptive containing 30 μg ethinyl estradiol and 150 μg levonorgestrel (Microgynon), and found that although women using the oral contraceptive had higher peak serum levels of estradiol than the other two agents, users of the transdermal patch had an overall higher exposure to estrogen (AUC or "area under the curve") than users of the other two formulations. The authors state that a lower exposure to ethinyl estradiol is desirable because of reduced "estrogen-related side effects..."

However, the term "estrogen exposure" that is used in the above study is actually a surrogate marker that the authors are using to predict the risk of estrogen-related adverse events with these products. No epidemiological data exist that demonstrate that the use of Ortho-Evra® results in higher rates of estrogen-associated adverse outcomes such as thromboembolic events. It is essential to have epidemiological information derived from rigorously performed clinical trials to make such clinical predictions. In the case of the three agents studied, the different doses and delivery systems likely are important for determination in the actual contraceptive effectiveness and safety. To this end, what if the peak concentration of ethinyl estradiol associated with the use of a contraceptive (Cmax) turns out to be the most important predictor of adverse outcomes instead of the area under the curve? Only epidemiological data will provide an accurate comparison of clinical risks between transdermal and other contraceptives. In fact, the new language in the Ortho-Evra® package insert specifically states that it is not known whether the pharmacokinetic differences are associated with an increase in the risk of serious adverse events in women using the contraceptive patch compared with women using oral contraceptives containing 35 μg ethinyl estradiol. If the package insert is meant to provide clinical warning concerning the use of a particular drug, this statement, which appears in various forms throughout the package insert, truly defies logic.

Women who use Ortho-Evra®, or any other estrogen-containing contraceptives, have an increased risk of developing a thrombolic event. However, a greater increase in the risk of such events compared to users of combination oral contraception has thus far not been determined to be present in the more than 5 million women who have used Ortho-Evra®. Unfortunately, the assumption that will be made by many who read the new package insert language, the van den Heuvel et al. study and the resulting press releases is that the transdermal patch is associated with an even higher rate of adverse events because the "area under the (estrogen) curve" was greater than that observed with vaginal ring or oral contraceptive use. Indeed, a recent article in the Wall Street Journal reports that numerous physicians and clinics are actually encouraging women to consider other contraceptive options or to discontinue the use of the patch altogether. Why would clinicians do this without any clinical evidence of an increased risk of adverse events? And why would an organization or agency communicate such information knowing full well the likely response of many women's health care providers?


The article concludes:

[T]here is one fundamental fact that must be in the forefront of contraceptive study and practice: without epidemiological data to support a clinical correlation, outcomes from surrogate marker studies can result in poor clinical practice. The irony is that the women who should be the beneficiaries of these package inserts changes actually become the unknowing victims of poor clinical practice. Recommendations made in the absence of data on clinical outcomes may lead to choices that increase the likelihood of unintended pregnancy.

In addition to the potential harm of using surrogate markers to develop warning statements concerning the risks associated with the patch or any other contraceptive option, another potential adverse outcome of continuing this practice is the eventual loss of confidence in our regulatory agencies and professional organizations to provide accurate information for professionals and consumers alike. The continuing inappropriate use of nonclinical studies to formulate warnings about the safety of contraceptives and other drugs may result in an interpretation to disregard these warnings by professionals and the public that will obscure real clinical risk associated with a particular drug or device. The true risks may be obscured by the continuing barrage of innuendo and pseudo-science on the package inserts of many drugs and devices.

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Reproductive Health Risks

Interesting article on reproductive risks by Dr. Trussell in Contraception. [Not sure if you can access the article without a subscription, so I'll quote in full.]:

Volume 73, Issue 5, Pages 437-439 (May 2006)

Reproductive health risks in perspective

James Trussell

Beth Jordan

Dramatic headlines about women's health — deaths of women using the OrthoEvra patch, for example, or after medication abortion — can quickly lead patients and healthcare practitioners into a state of panic and uncertainty over the appropriate course of action to take. Should therapy be continued or not? What is the real risk of death?

Alarmist, misleading, inaccurate or incomplete media coverage is certainly a source of confusion, but such stylized reporting is not likely to be eliminated from most large media outlets in the near future. That fact, coupled with the lack of courses in biostatistics and risk-assessment analysis in most medical training programs and the reality that health professionals have little time to counsel patients about the risks of various treatments, can lead patients to make poor health-related choices.

This danger is particularly worrisome when patients are dealing with contraceptive issues and the threat of an unplanned pregnancy. Doctors, nurses and other providers have little time to investigate and consolidate risk-related information for their patients, and patients have few resources available to help them ascertain the risks from using various contraceptive methods. The brief summary provided here is intended to help inform clinicians and their patients of the risk of death from pregnancy, abortion and the use of various forms of hormonal contraception, as well as from other voluntary activities.

In general, contraceptives pose few serious health risks to users. Moreover, the use of contraceptive methods is generally far safer than pregnancy. Unintended pregnancies unnecessarily place women at risk. Women in many developing countries will experience an even greater advantage in using contraceptive methods than those in the developed world in comparison with pregnancy-related mortality. Nonetheless, use of some contraceptive methods may entail potential risks.

• Use of the method may lead to serious outcomes such as death, hospitalization, surgery, medical side effects, infections, loss of reproductive capacity or pain.

• Contraceptive failure (pregnancy) is associated with risk: a woman must assess the likelihood of contraceptive failure and the dangers that a pregnancy would pose.

• Future fertility may be influenced by choice of a contraceptive method.

When it comes to the most serious outcome of all — death — the absolute level of risk is extraordinarily low for most women. Table 1 puts into perspective some of the risks of everyday life in the United States [1–9]. Other major health risks from contraceptive use are not only uncommon, but they are also most likely to occur in women who have underlying medical conditions.


Table 1.

Everyday risks in perspective

ActivityRisk of deathSource
Risk per year
While skydiving1 in 1000Laudan [1]
From an accident1 in 2900
From an automobile accident1 in 5000
From a fall1 in 20,000
From a fire1 in 50,000
From riding your bicycle1 in 130,000
In an airplane crash1 in 250,000
From being struck by lightning1 in 2,000,000
Risk per year for women preventing pregnancy
Using OCs Schwingl et al. [2]
Nonsmoker
Aged 15–34 years1 in 1,667,000
Aged 35–44 years1 in 33,300
Smoker
Aged 15–34 years1 in 57,800
Aged 35–44 years1 in 5200
Undergoing tubal sterilization1 in 66,700Escobedo et al. [3]
Risk per year from using tampons1 in 5,734,000Hajjeh et al. [4]; U.S. Census Bureau [5]
Risk from pregnancy1 in 8700Berg et al. [6]
Risk from spontaneous abortion1 in 142,900Saraiya et al. [7]
Risk from legal induced abortion
Mifepristone/misoprostol1 in 110,000Summers [8]
Surgical1 in 142,900Bartlett et al. [9]
≤8 weeks1 in 1,000,000
9–10 weeks1 in 500,000
11–12 weeks1 in 250,000
13–15 weeks1 in 58,800
16–20 weeks1 in 29,400
≥21 weeks1 in 11,200


Pregnancy

The risk of death from pregnancy and delivery is about 1 in 8700, lower than the annual risk of death from an automobile accident but higher than the annual risk of death from use of combined oral contraceptives (OCs) for all women except those aged 35–44 years who smoke and higher than the risk of death from abortion, even at gestational ages ≥21 weeks.

Combined OCs

Combined OCs have been associated with an increased risk of myocardial infarction (MI) and stroke. Smoking definitely increases the risk of MI, especially in women older than 35 years. However, nonsmoking, normotensive, nondiabetic women of any age who use combined OCs are not at increased risk for MI. The risk of stroke in nonsmoking women younger than 35 years is not increased by use of OCs with less than 50 μg of estrogen [10]. The risk of venous thromboembolism is increased by combined OC use, but the absolute risk of this increase is quite low among women who use OCs with less than 50 μg of estrogen, ranging from 9 events per 100,000 women-years of exposure among those aged 20–24 years to 18 events per 100,000 women-years of exposure among those aged 40–44 years [10].

Use of combined OCs is associated with a decreased risk of cancers of the endometrium and ovary and an increased risk of cancer of the cervix and liver, a small increased risk of breast cancer in young women and a decreased risk of colorectal cancer [10]. However, there is great uncertainty regarding the causal link, if any, between combined OC use and liver and colorectal cancer [10], and recent evidence suggests no association between current or former combined OC use and breast cancer [11]. Regardless, the net effect of pill use on cancer is negligible [10].

Persistent infection with certain types of human papillomavirus (HPV) is the most frequent cause of cervical cancer. However, the incidence of cervical cancer is increased in women using OCs, particularly long-term users, even among women infected with HPV; this risk increases as duration of use increases [12]. Results from limited data also suggest a slight increase in the risk of cervical cancer among women who use injectable contraceptives for 5 years or longer [12].

Analysis of pooled data from 54 epidemiologic studies conducted in 25 countries found that women have a slightly increased risk (about 25% higher) for having breast cancer diagnosed while they are using OCs. Cancers diagnosed in these women are less advanced clinically than those diagnosed in women of the same age who have never used OCs [13]. The increased risk is apparent soon after pill use begins but does not increase with duration of use, declines after use ceases and does not persist beyond 10 years after exposure ceases. These patterns are not typical for a carcinogenic agent but would be consistent with promotion of already existing tumors or with earlier diagnosis of breast cancer in women who have used the pill. A more recent study in the United Sates found that among women aged 35–64 years, current or former combined OC use is not associated with an increased risk of diagnosis of breast cancer [11].

OrthoEvra patch

The OrthoEvra patch has been recently highlighted in the press after the Food and Drug Administration (FDA) announced a label change in October 2005. The change includes a bolded "warning" indicating that use of the patch entails a 60% higher exposure to estrogen than use of a typical combined OC containing 35 μg of estrogen; however, the FDA states that the clinical relevance of this finding is unknown [14].

The actual risk of death from patch use is impossible to determine. Spontaneous reports of deaths of women using the patch have been received by the FDA. Spontaneous reports to the FDA can come from various sources, and the quality and extent of the information reported vary considerably. It is often unclear whether a death is causally related to use of a drug. Moreover, even if the intensive follow-up was to establish that a certain number of deaths were likely to have been caused by use of that drug, there remains the problem of computing an accurate mortality rate because the relevant denominator is also not known. Therefore, it is not possible to know at this time how the mortality risk from use of the patch compares with that from use of combined OCs [15].

Abortion

The risk of death is about the same from medication abortion and from surgical abortion; however, the risk of death from surgical abortion is greatest for higher gestational ages where medication abortion is not used. Nevertheless, induced abortion is safer than continuing pregnancy and entails about the same risk as spontaneous abortion.

Conclusion

As sensationalized news reporting becomes more common and thoughtful analysis becomes more difficult to find, given its perceived lack of appeal to media observers, healthcare practitioners must intensify efforts fully and repeatedly to inform patients of their true risks of death from various contraceptive methods. This imperative is particularly important as the FDA has become extremely sensitive regarding drug safety warnings.

Women are far more likely to die from pregnancy-related complications, from automobile accidents or from a fall than they are from using hormonal contraception or having undergone either a medication or surgical abortion. Those who claim that hormonal contraception and abortion are unsafe base this assertion on ideology, not evidence-based science. The evidence in Table 1 shows otherwise.



References

1. Laudan L. The book of risks. New York: John Wiley and Sons; 1994;.

2. Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol. 1999;180:241–249. Abstract

3. Escobedo LG, Peterson HB, Grubb GS, Franks AL. Case-fatality rates for tubal sterilization in U.S. hospitals, 1979–1980. Am J Obstet Gynecol. 1989;160:147–150. MEDLINE

4. Hajjeh RA, Reingold A, Weil A, Shutt K, Schuhat A, Perkins BA. Toxic shock syndrome in the United States, 1979–1996. Emerg Infect Dis. 1999;5:807–810. MEDLINE

5. U.S. Bureau of the Census . Statistical abstract of the United States: 2003. Washington (DC): Government Printing Office; 2003;[Table 11].

6. Berg CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancy-related mortality in the United States, 1991–1997. Obstet Gynecol. 2003;101:289–296. MEDLINE

7. Saraiya M, Green CA, Berg CJ, Hopkins FW, Koonin LM, Atrash HK. Spontaneous abortion-related deaths among women in the United States — 1981–1991. Obstet Gynecol. 1999;94:172–176. MEDLINE

8. Personal communication from Danco Laboratories, C Summers. 9 March 2006.

9. Bartlett LA, Berg CJ, Shulman HB, et al.. Risk factors for legal induced abortion-related mortality in the United States. Obstet Gynecol. 2004;103:729–737. MEDLINE

10. Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190(Suppl):S5–S22. Abstract

11. Marchbanks PA, McDonald HG, Wilson HG, et al.. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025–2032.

12. [12]Smith JS, Green J, Berrington de Gonzalez A, et al.. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet. 2003;361:1159–1167. Abstract

13. Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713–1727. MEDLINE

14. Ortho-McNeil Pharmaceutical. Ortho Evra Product labeling. Revised November 2005.

15. Media report on Ortho Evra patch sets off safety concerns in women. Contracept Technol Update. 2005;26:113–115.

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