Warnings on venous thromboembolism risks may have been premature
New data may lead to change in use of third-generation OCs
Clinicians in the United States who have been concerned about prescribing oral contraceptives with the third-generation progestin desogestrel now have new food for thought in weighing the risks and benefits for their patients. Findings presented at the recent International Federation of Gynecology and Obstetrics (FIGO) conference in Denmark show that "the risk of venous thromboembolism (VTE) among users of OCs with third-generation progestins, as compared with users of second-generation progestins, may be less than initially reported."
This statement was issued by FIGO and signed by Sven Skouby, MD, DSci, and Øjvind Lidegaard, MD, department of OB/GYN in the University of Copenhagen; Daniel Mishell, MD, department of OB/GYN in the University of Southern California in Los Angeles; and John Guillebaud, MA, FRCSE, FRCOG, MFFP, medical director of the Margaret Pyke Family Planning Centre in London.
Based on Lidegaard’s study findings1 presented at the conference and supported by other recently published research, the risk for VTE with third-generation pills containing desogestrel or gestodene (not available in the United States) may not be as high as the doubled risk first reported in 1995, Guillebaud says.
Lidegaard’s soon-to-be published study looks at the discharges of Danish hospital patients with venous thromboembolism. This study is especially strong, says Guillebaud, because all hospital discharges in Denmark are tracked, giving the study a very defined population with a strong response rate.
"On the basis of this standard case control study, where they were looking at the discharges of patients with venous thromboembolism and matched controls, they found that the risk ratio comparing third- against second-generation [pills] was initially 1.77, but when they controlled for duration of use, it dropped to 1.44 and was no longer statistically significant," he notes. "That is the reason for saying in our press release that the risk of venous thromboembolism may be less than initially reported because even if it were statistically significant, the figure 1.44 is less than 1.77 and certainly less than the 2 that was shown by four sets of studies,2,3,4,5,6 the basis for the warnings that were issued by the British Committee on Safety of Medicines."
Aftermath of the pill scare
The committee’s public notice on the increased risk of VTE and third-generation pills containing gestodene or desogestrel set off a wave of controversy in late 1995. Numerous British women switched or stopped their pills following the warning, which led, in many areas, to an increase in abortions.7 (For further background, see the following issues of Contraceptive Technology Update: January 1996, pp. 6-10; April 1996, pp. 41-2, 47; November 1996, pp. 142-3; and December 1996, p. 149.)
Although the U.S. Food and Drug Admini stration issued a statement that the risk of VTE was not sufficient to warrant switching patients from desogestrel pills, many clinicians shied away from such formulations. Only two pills sold in the United States contain the progestin desogestrel: Desogen from Organon in West Orange, NJ, and Ortho-Cept from Ortho-McNeil Pharmaceuticals in Raritan, NJ.
Ortho-Cept subsequently dropped from its 1995 top spot in CTU’s annual Pill Survey to fifth place in 1996. Desogen witnessed the same slide, dropping from sixth place in 1995 to ninth place in 1996. Both OCs held their 1996 positions in the 1997 report. (Pill Survey reports were included in the following issues of CTU: September 1995, October 1996, and November 1997.)
Review recent papers for information
After publication of the initial third-generation studies, some expressed concerns, says Andrew Kaunitz, MD, professor and assistant chair of OB/GYN at the University of Florida Health Sciences Center in Jacksonville.
"First, given our knowledge regarding the impact that estrogen has on the coagulation system, it is not biologically plausible that the progestin component of an OC should impact VTE risk," he says. "Second, investigators in these initial studies did not appear to have assessed whether or not women prescribed desogestrel OCs may have been intrinsically at higher risk for VTE than women prescribed other OCs."
Clinicians will want to review the full findings of Lidegaard’s study when it is published in the British Medical Journal, as well as look over other current research, in assessing their position on the matter, say Guillebaud and Mishell.
"Personally, I don’t think that we can discount the earlier studies yet," notes Guillebaud. "I think there may be a differential, but it’s probably less than what was reported, as we said in our press release."
Mishell points to a study of data from the General Practice Research Database, operated by the Department of Health in London, that could not find an increased risk of VTE among users of third-generation OCs when researchers matched cases closely for age and duration of use of products.8
"The consensus of opinion is that the increased risk of venous thrombosis found among third-generation users is most likely due to confounding factors, such as duration of use of the pill and also prescribing bias. Many clinicians preferentially prescribed the newer formulations to women at risk for cardiovascular disease," Mishell says.
Kaunitz concurs with Mishell’s assessment, saying, "Subsequent publications8,9 have added strong evidence that prescribing bias may account for much or even all of the difference in VTE risks with various OC formulations reported earlier."
Look at risks, benefits of pills
It is important to frame the risks of VTE in the overall health of women. Even if the risk is real, the increased risk of thromboembolism is still less than that associated with pregnancy.10 Furthermore, mortality risk associated with VTE is low.
"We’re talking about a condition which fortunately only has a 1% to 2% mortality, and even if you take the view that there is some increased risk of venous thromboembolism, the differential in mortality for the two types of pills in a million users would only be 1 to 2 per million," Guillebaud explains.
New information, such as a study published in a recent American Journal of Obstetrics and Gynecology, indicates that desogestrel OCs may be safer than older formulations with respect to myocardial infarction risks, says Kaunitz.11 This area requires more study, he notes.
Guillebaud agrees, noting that recent data12 released by the Potsdam, Germany-based Trans national Research Group on Oral Contracep tives and Health of Young Women suggest similar outcomes.
What do all of these findings mean for the clinician and the patient?
"What I teach is that if you are dealing with a woman who has a venous risk factor, such as obesity or severe varicose veins, then you would still recommend not using pills with desogestrel," Guillebaud explains. "But if she is a heavy smoker or a diabetic, or has blood pressure problems or any of the other standard risk factors for arterial disease, including myocardial infarction, then you would be likely to consider switching her to desogestrel pills as she approaches the older reproductive ages in which the risk of arterial disease becomes more significant than that of venous disease." (For further details on Guillebaud’s reasoning, see story, p. 148.)
It all comes down to the patient sitting in front of you, Guillebaud concludes. Counsel her about the risks and benefits of second- and third-generation OCs, and let her choose the pill.
"All of these differential risks between [second- and third-generation] pills are so small that after counseling, if a woman chooses any brand for herself because she simply feels better on it, she may do so," he notes. "If she is fully informed about present knowledge and the uncertainties and is prepared to take a possible extra VTE risk, she should be allowed to do so."
(Guillebaud and Kaunitz offer approaches to determining candidates for third-generation pills. See story, p. 148.)
References
1. Edstrom B, Lidegaard O. Venous thromboembolism and oral contraceptives. A case control study. Presented at the 15th FIGO World Congress of Gynecology and Obstetrics, Copenhagen, Denmark; Aug. 7, 1997.
2. World Health Organization Collaborative Study on cardiovascular disease and steroid hormone contraception. Effect of different progestins in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346:582-588.
3. World Health Organization Collaborative Study on cardiovascular disease and steroid hormone contraception. Venous thromboembolic disease and combined oral contraceptives: Results of international multicentre case-control study. Lancet 1995; 346:575-582.
4. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346:1,589-1,593.
5. Spitzer WO, Lewis MA, Heinemann LAJ, et al. Third-generation oral contraceptives and risk of venous thromboembolic disorders: An international case-control study. BMJ 1996; 312:83-87
6. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing third-generation progestagen. Lancet 1995; 346:1,593-1,596.
7. Szarewski A. Third-generation pill warnings were premature. Lancet 1997; 350 (9076).
8. Farmer RDT, Lawrenson RA, Thompson CR, et al. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349:83-88.
9. Lewis MA, Heinemann LAJ, MacRae KD, et al. The increased risk of venous thromboembolism and the use of third-generation progestagens: role of bias in observational research. Contraception 1996; 54:5-13.
10. Grimes DA, ed. Risk of venous thromboembolism with third-generation OCs. Contraceptive Report 1996; 2:15.
11. Rosenberg L, et al. Modern oral contraceptives and cardiovascular disease. Am J Obstet Gynecol 1997; 177:707-715.
12. Lewis MA, Heinemann LAJ, Spitzer WO, et al. 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. Contraception 1997; 56:129-40.
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