Web site: December 1998
Prescriber Update No.17:12-15
Medsafe Editorial Team
At least 6 New Zealand women aged 19-32 years who were taking third generation oral contraceptives (OCs) containing desogestrel or gestodene have died of pulmonary embolism during the period January 1993 to June 1998. In some cases the woman had obesity, immobilisation, leg injury or evidence of old thromboembolic activity. Other cases had recent symptoms of possible deep vein thrombosis.
These cases highlight:
At least 6 women have died of pulmonary embolism with third generation pills
Epidemiological studies provide best measure of rate of VTE
Symptoms of recent thromboembolic activity, or risk factors in fatalities
Continue to observe prescribing advice issued July 1996
Evaluate women for risk factors for VTE
Advise women to report thromboembolic events immediately
Report cases of VTE to CARM
Up to mid 1998, 6 reports of death from pulmonary embolism with OCs had been received in New Zealand (ages 19-32; median 26 years). In each case the woman was taking one of the third generation pills containing desogestrel or gestodene. No deaths have been reported in association with other OCs. The third generation pills available in New Zealand are Femodene, Marvelon, Mercilon and Minulet. Four of the deaths occurred during the 18-month period from January 1997 to June 1998.
In July 1996, the Ministry of Health published1 prescribing advice based on published evidence2-5 that the risk of venous thromboembolism (VTE) was higher by a factor of approximately 2 with the third generation pills than with the combined low dose OCs containing levonorgestrel or norethisterone (absolute risk 2 in 10,000 woman-years vs 1 in 10,000 woman-years). Medical practitioners were advised to consider prescribing one of the latter in preference to one of the third generation pills.
At the time of publication of this advice it was estimated that the annual number of New Zealand cases of VTE from the use of contraceptives containing desogestrel or gestodene was 40 (approx. usage 150,000 women). At a case fatality rate of 1-2% and continued usage at this level, a death would be expected every 1.5 to 2.5 years. Four deaths in 18 months is an unexpectedly high number. The actual number may be higher, because it is unlikely that all cases have been reported. The reason for this high number is unclear.
The total number of reports of fatal and nonfatal VTE received by the Centre for Adverse Reactions Monitoring (CARM) since 1987 is 46 for third generation pills and 9 for other low dose pills. 16 of 17 reports of pulmonary embolism are associated with third generation pills. Diane 35 has been associated with 8 reports of VTE, of which 3 were pulmonary embolism, but none resulted in death.
While the CARM data indicate that VTE and death from pulmonary embolism in young women taking OCs are a real problem, the data are subject to natural fluctuation and reporting bias. The results of the epidemiological studies concerning rates of VTE with the different types of OCs provide a more reliable estimate than CARM data.
Internationally there is debate about the status of the epidemiological evidence for a higher rate of VTE with the third generation OCs. Some experts6 claim that the studies cited above are subject to bias and confounding factors to the degree that the observed difference in rate of VTE is little more than an artefact. However, after an exhaustive review, the Scientific Group on Cardiovascular Disease and Steroid Hormone Contraception of the WHO concluded7 at the end of 1997:
Combined OC preparations containing desogestrel and gestodene probably carry a small risk of venous thromboembolism beyond that attributable to combined OCs containing levonorgestrel.
Medsafe and the Medicines Adverse Reactions Committee (MARC) continue to hold the view that there is a higher risk of VTE with the third generation pills than with other low dose pills. They also believe the prescribing advice issued in July 1996 is still appropriate. The MARC considers new data as it becomes available and expects to be reviewing significant new data at its first meeting in 1999.
An analysis of the fatalities is of interest. In 2 women, there had been symptoms of possible recent thromboembolic activity, in the form of pain in a leg or legs. Another who was slightly obese had evidence at autopsy of thromboembolic activity in the lungs in recent days or weeks. A fourth woman had evidence of an old pulmonary embolism. In the remaining two women, recent injury may have played a part. One of the women was immobilised due to a knee injury. The post-mortem found a thrombosis in the calf of the injured leg. The sixth woman who was obese had injured her left knee 5 months previously, and had thrombosis in a vein of the calf of the left leg.
Hence, only one woman had reason for combined OCs to be contraindicated, and for this woman her previous pulmonary embolism may have been silent.
These cases highlight:
The advice the Ministry issued in July 1996 should continue to be observed.1,8 Medical practitioners are recommended to consider prescribing a low dose OC containing levonorgestrel or norethisterone where a combined OC is appropriate and the woman has no contraindications. The other combined low dose pills available in New Zealand are Brevinor, Microgynon 30, Monofeme, Norimin, Nordette, Synphasic, Trifeme, Triphasil and Triquilar. In the absence of thromboembolic risk factors, a woman’s choice of a third generation OC, for whatever reason, should be respected.
Prior to prescribing an OC, the doctor should check the woman for risk factors for VTE which include a family history of VTE, personal history of VTE, hereditary thrombophilia, extensive varicose veins, obesity (body mass index ≥ 30 kg/m²), lupus anticoagulant, malignancy and long term immobility. A personal history of VTE and hereditary thrombophilia are both contraindications for OCs containing an oestrogen. Temporary risk factors may also increase the risk of VTE. These include immobility (because of illness or during a long international flight), surgery (during and in the recovery period), trauma and dehydration.
Alternative means of contraception such as progestogen-only pills should be used in women with contraindications for oestrogen-containing OCs. Women with a risk factor for VTE should be advised to use an OC not containing desogestrel or gestodene, or to use an alternative method of contraception.
Although some thromboembolic events occur without symptoms, women taking an OC containing an oestrogen should be advised of the possible symptoms. They should be advised to be more alert to such symptoms following injury or surgery, or during immobilisation, and in these circumstances particularly to report the symptoms immediately to a medical practitioner. The symptoms of leg thrombosis include pain, heat and swelling, but many occur without symptoms. The most common, and often the only, symptom of pulmonary embolism is the sudden onset of unexplained dyspnoea. Other symptoms are tachypnoea and pleuritic chest pain.
VTE with oral contraceptives is an adverse reaction of current concern. Any New Zealand cases of VTE occurring with oral contraceptives should be reported to the New Zealand Centre for Adverse Reactions Monitoring. It is particularly important that deaths are reported.