Skip to main content

Nonoral Hormonal Contraception Linked With Increased Risk for Venous Thrombosis


CLINICAL CONTEXT

Several studies have evaluated the risk for venous thrombosis, including deep vein thrombosis and pulmonary embolism, in women using oral contraceptive pills. However, few data are available regarding the risk for venous thrombosis in users of nonoral hormonal contraceptives.
To prevent pregnancy, nonoral hormonal contraceptives continuously release hormones into the body. The objective of this study by Lidegaard and colleagues was to determine the risk for venous thrombosis in current users of nonoral hormonal contraception.

STUDY SYNOPSIS AND PERSPECTIVE

Women who use transdermal patches or vaginal rings for contraception may be at significantly increased risk for venous thromboembolism compared with women who do not use hormonal contraception, according to a national registry-based Danish study published online May 10 in the BMJ.
Women using transdermal patches had a relative risk (RR) of 7.9 (95% confidence interval [CI], 3.5 - 17.7) for deep vein thrombosis and pulmonary embolism compared with women not using hormonal contraception after adjusting for age, calendar year, and education. Similarly, women using vaginal rings had an RR of 6.5 (95% CI, 4.7 - 8.9) compared with nonusers. In contrast, women taking oral hormonal contraceptives had a 3.2-fold increase (95% CI, 2.7 - 3.8) relative to women not using hormonal contraception.
The incidence for venous thrombosis was 2.1 events/10,000 woman-years in nonusers, 9.7 events/10,000 woman-years for those using contraceptive patches, 7.8 events/10,000 woman-years for those using the vaginal ring, and 6.2 events/10,000 woman-years for those using oral hormonal contraception.
Given the increased RR for women using nonoral versus oral hormonal contraception, Øjvind Lidegaard, MD, from the University of Copenhagen, Denmark, and colleagues conclude that women should switch to oral contraception to reduce their risk for deep vein thrombosis and pulmonary embolism.
Melissa Gilliam, MD, MPH, from the Department of Obstetrics and Gynecology at the University of Chicago, Illinois, suggests a more balanced approach: "I think it is important to put these things in perspective and include a thorough discussion of health benefits, cancer prevention, and general safety of these methods," Dr. Gilliam said to Medscape Medical News.
"I generally prescribe second-generation progestin birth control pills because they are cheapest. In addition, I always counsel my patients about the risk of blood clots and that it might be slightly higher with some methods rather than others, and I give them the numbers so they can see they are overall low...but I also explain that the risk of clot is still higher with pregnancy, so if after counseling about all methods they really feel as if the patch and the ring are their best options, they are still at lower risk of a clot than if they were to become pregnant," Dr. Gilliam added, noting the importance of considering other options.
"I find in my young population, the biggest issue is adherence, so I try to counsel them for long-acting methods like the [intrauterine device], as it is not thrombogenic and most likely to prevent pregnancy," Dr. Gilliam said.
Indeed, the authors found that women using the levonorgestrel intrauterine device demonstrated a significant decrease in risk for venous thrombosis, even relative to those not using hormonal contraception at all.
More Than 1.5 Million Women Studied for 10 Years
For the study, the researchers obtained data from 4 Danish national registries for 1,626,158 thrombosis-free nonpregnant women aged 15 to 49 years from January 2001 to December 31, 2010.
During 9,429,128 woman-years of follow-up, 5287 cases of venous thrombosis were recorded, 3434 of which were confirmed, for an adjusted incidence rate of 2.1/10,000 woman-years.
The increased risk associated with nonoral hormonal contraceptives may be explained by the 3- and 5-fold increase in sex hormone–binding globulin and the 3.75-fold increase in activated protein C sensitivity among vaginal ring users, the authors note.
Moreover, the authors note that the results are supported by pharmacokinetic studies showing 60% higher levels of estrogen among women using the patches compared with the corresponding oral contraceptive.
Progestogen-only subcutaneous implants showed a trend for increased risk for thrombosis (RR, 1.4; 95% CI, 0.6 - 3.4) compared with women not using hormonal contraception, and a nonsignificant decline in risk (RR, 0.4; 95% CI, 0.2 - 1.1) compared with those using levonorgestrel-containing contraceptives.
"The modest non-significant 40% increased relative risk of venous thrombosis in women using subcutaneous implants is not surprising," the authors write, noting that other types of progestogen-only contraceptives do not confer increased risk.
This was confirmed among women using the levonorgestrel intrauterine device, which decreased the risk for venous thrombosis by 40% relative to nonusers of hormonal contraceptives and by 80% for those taking combination pills, respectively (RR, 0.6; 95% CI, 0.4 - 0.8; RR, 0.2; 95% CI, 0.1 - 0.3, respectively).
The protective influence of progestin-only contraception may depend on dose, the authors suggest.
Study limitations include a lack of data regarding body mass index (adiposity is a well-documented risk factor for venous thrombosis) and information on smoking status, a weak factor among young women.
"[W]e have no reason to believe in preferential prescribing of specific types of hormonal contraception among smokers," the authors explain. "In Denmark the correlation between smoking and length of education is strong. Thus, controlling for years of schooling and length of education may have captured most confounding (if any) influenced by smoking."
Should Women Switch to Combination Oral Contraceptives?
The clinical implications of these findings can be expressed as the number of women who should switch from the transdermal patch or vaginal ring to combination oral contraceptives containing levonorgestrel to avoid an event of venous thromboembolism.
If the incidence rates of venous thromboembolism in women using combination oral contraceptives containing levonorgestrel, the vaginal ring, and contraceptive patch are 6, 11, and 14 per 10,000 exposure years, respectively, 2000 women using the ring and 1250 using the patch would have to switch to oral contraceptives to prevent a single event during the course of 1 year.
"[W]omen are generally advised to use combined oral contraceptives with levonorgestrel or norgestimate, rather than to use transdermal patches or vaginal rings," the authors conclude.
"This is an important study...larger sample size is very helpful in considering the overall implications and generalizability of the results," Lisa Kane Low, PhD, CNM, FACNM, director of midwifery education from the University of Michigan School of Nursing, Ann Arbor, told Medscape Medical News in an interview, noting the importance of keeping perspective on the overall low risk for venous thrombosis while balancing the seriousness and implications of such an event.
"Women's healthcare providers will need to incorporate this new evidence of comparative risk of contraceptive methods into their counseling as they work with women to select the optimal contraceptive method for their individual situation," Dr. Low concluded, noting that the risks associated with oral hormonal contraceptives are better known than that of newer, nonoral methods.
The study was supported by the Gynaecological Clinic, Juliane Marie Center, Rigshospitalet. Dr. Lidegaard has disclosed receiving speech honorariums from Bayer Pharma Denmark, MSD Denmark, and Theramex during the last 3 years; he also has served as an expert witness in a US legal case. One coauthor has had congress expenses paid by pharmaceutical companies twice during the last 3 years. Dr. Gilliam and Dr. Low have disclosed no relevant financial relationships.

Comments

Post a Comment

Popular posts from this blog

Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."

May 23, 2012   (Updated May 24, 2012)  (Silver Spring, Maryland)  —  The missing data issues plaguing the  ATLAS ACS 2 TIMI 51   trial of the factor Xa inhibitor  rivaroxaban  (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the  FDA  Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus  clopidogrel , or  ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the  ATLAS ACS TIMI 46   phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
Post a Comment
Read more

Antidepressants Linked to Higher Diabetes Risk in Kids

Pediatric patients who use antidepressants may have an elevated risk for type 2 diabetes, the authors of a new study report. In a retrospective cohort study of more than 119,000 youths 5 to 20 years of age, the risk for incident type 2 diabetes was nearly twice as high among current users of certain types of antidepressants as among former users, Mehmet Burcu, PhD, and colleagues report in an article  published online October 16 in  JAMA Pediatrics . The risk intensified with increasing duration of use, greater cumulative doses, and higher daily doses of these antidepressants. The findings point to a growing need for closer monitoring of these products, including greater balancing of risks and benefits, in the pediatric population, the authors caution. They undertook the study because, despite growing evidence of an association between antidepressant use and an increased risk for type 2 diabetes in adults, similar research in pediatric patients was scarce. "To our know...
Post a Comment
Read more

Contact Precautions May Have Unintended Consequences

Contact precautions, including gloves, gowns, and isolated rooms, have helped stem the transmission of hospital pathogens but have also had some negative consequences, according to findings from a new study. Healthcare worker (HCWs) visited patients on contact precautions less frequently than other patients and spent less time with those patients when they did visit, report Daniel J. Morgan, MD, from the University of Maryland School of Medicine and the Veterans Affairs (VA) Maryland Health Care System, Baltimore, and colleagues. Moreover, patients on contact precautions also received fewer outside visitors. "Less contact with HCWs suggests that other unintended consequences of contact precautions still exist," Dr. Morgan and coauthors write. "The resulting decrease in HCW contact may lead to increased adverse events and a lower quality of patient care due to less consistent patient monitoring and poorer adherence to standard adverse event prevention methods (such...
Post a Comment
Read more