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EMEA and third-generation oral contraceptives
THE LANCET
as hepatitis C and other non-A, non-B hepatitis. An early decision on liver transplantation in hepatitis-Eassociated fulminant hepatic failure may therefore be unjustified. The question of whether the medication that both our patients were taking (oestrogen-containing oral contraceptives and antimalarials) contributed to the development of fulminant hepatic failure is intriguing but speculative *J G Zijlstra, E B Haagsma, J E Tulleken, T S van der Werf Intensive and Respiratory Care Unit and Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Groningen, 9700 RB Groningen, Netherlands
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Mas A, Rodés J. Fulminant hepatic failure. Lancet 1997; 349: 1081–85. Khuroo MS, Teli MR, Skidmore S, Sofi Ma, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981; 70: 252–55. Tsega E, Hansson BG, Krawczynski K, Nordenfelt E. Acute sporadic viral hepatitis in Ethiopia: causes, risk factors, an effect on pregnancy. Clin Infect Dis 1992; 14: 961–65. Verschuuren EAM, Haagsma EB, Zijlstra JG, Stegeman CA. Non-oliguric acute renal failure associated with hepatitis E. Nephrol Dial Transpl 1997; 12: 799–801. Verschuuren EAM, Haagsma EB, Zijlstra JG. Fulminant leverfalen door hepatitis E en de indicatie voor levertransplantatie. Intensive Care Rev 1996; 11: 109–12.
EMEA and third-generation oral contraceptives SIR—Jan P Vandenbroucke and Frits R Rosendaal (April 19, p 1113)1 refer to the cross-sectional study by Rosing et al2 which reported an association between the use of oral contraceptives (OCs) and functional resistance to the natural anticoagulant, activated protein C (APC); they found greater APC resistance among women using “third generation” OCs than among those who used second-generation OCs. According to Vandenbroucke and Rosendaal, those results “fit admirably with the epidemiological data”, showing that the incidence of deepvenous thrombosis and pulmonary embolism (VTE) is about twice as high in users of third-generation OCs as in second-generation OC users. They wonder why the results of the epidemiological studies have apparently been ignored by the European Agency for the Evaluation of Medicinal Products (EMEA); they suggest that EMEA experts have focused on irrelevant arguments made redundant by further analyses; and they seek the involvement of “independent consumer boards or patient platforms in drugsafety regulation” who might be able to resist pressure better.
290
The comparative safety of secondgeneration and third-generation OCs was addressed by the scientific committee of EMEA (the CPMP) in October, 1995, and again, after the publication of the first four epidemiological studies, in December, 1995, and in January, 1996. CPMP set up a working group (including experts in pharmacoepidemiology, clinical pharmacology, obstetrics and gynaecology, cardiology, haemostasis, and biostatistics) which continues to hold regular meetings to analyse all new data. CPMP’s evaluation of the epidemiological evidence was set out on Jan 22, 1997. At that time, seven studies had been presented to CPMP. The risk of VTE was higher in women who used desogestrel or gestodene containing OCs (third generation) than in women using OCs containing levonorgestrel (the majority), lynoestrol, or norethisterone. The increased risk was about two-fold in the first four studies (and significant in three). In the next three studies, the risk difference was less; one was reported as an interim analysis,3 one reached statistical significance,4 and the other did not.5 Because of possible confounding biases, CPMP asked for further data and analyses from the investigators and from the marketing authorisation holders. However, not all the relevant information was available to the investigators so the impact of bias and confounding could not be fully evaluated. Nonetheless, the difference in risk decreased with increasing control for factors that could constitute confounders and introduce bias. The apparent absolute increase in risk of VTE is low even in third-generation OC users, and the case fatality rate is also low. The emergence of a new possible biological explanation (ie, decreased APC sensitivity) in no way permits “immediate separation of epidemiological chaff from wheat”. A mechanism for an association between a medicinal product and a risk strengthens the probability of a causal relation but does not prove it. The new method for measuring thrombin formation needs further validation and a more analytical approach than a cross-sectional study. The risk of VTE is linked to the balance between activation of the coagulation system and the fibrinolytic system, so simultaneous measurement of fibrinolytic activity is needed. One such study planned, at CPMP’s initiative, will include measurement of APC resistance (by the current method and by Rosing’s new method) at the same time in the menstrual cycle. The study will be done by the three manufacturers of third-generation OCs.
An assessment of the risks and benefits of OCs must take into account arterial complications such as myocardial infarction and stroke. Third-generation OCs might have an advantage here. CPMP has asked investigators to pool the WHO and the Transnational Study data to achieve better statistical power. In general, it would be valuable to know more about what risks patients are willing to take to attain certain benefits, once these have been reasonably well established. However, the regulatory process would probably benefit more from such knowledge than from direct involvement of “consumer boards”. CPMP and its ad hoc group will continue to assess the data and will recommend such regulatory measures as may be necessary. *J M Alexandre, K Strandberg *CPMP, EMEA, 7 Westferry Circus, London E14 4HB, UK; and Ad hoc Expert Group on Third Generation Oral Contraceptives and Cardiovascular Risks, CPMP
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Vandenbroucke JP, Rosendaal FR. End of the line for “third-generation-pill” controversy? Lancet 1997; 349: 1113–14. Rosing J, Tans G, Nicolaus GA, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and thirdgeneration oral contraceptives. Br J Haematol 1997; 97: 233–38. Lidegaard O. Oral contraceptives and venous thromboembolism: an epidemiological review. Eur J Contracept Reprod Health Care 1996; 1: 13–20. Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Populationbased study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–88. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995; 15: 195–200.
Home blood-pressure control in Japanese hypertensive population SIR—Giuseppe Mancia and colleagues (Feb 15, p 454)1 suggest that among the Italian hypertensive population, the number of patients with inadequate blood-pressure control is high not only when assessed in the clinic but also when assessed at home. We have investigated blood-pressure control at home among hypertensive patients living in Kahoku, a rural Japanese town.2 Our study comprised 2582 adults (1017 aged 25–64 years, 1565 aged ⭓65 years), which was 52% of the eligible adult population of Kahoku. We defined home blood pressure as the mean value of 20 home measurements
Vol 350 • July 26, 1997
as hepatitis C and other non-A, non-B hepatitis. An early decision on liver transplantation in hepatitis-Eassociated fulminant hepatic failure may therefore be unjustified. The question of whether the medication that both our patients were taking (oestrogen-containing oral contraceptives and antimalarials) contributed to the development of fulminant hepatic failure is intriguing but speculative *J G Zijlstra, E B Haagsma, J E Tulleken, T S van der Werf Intensive and Respiratory Care Unit and Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Groningen, 9700 RB Groningen, Netherlands
1 2
3
4
5
Mas A, Rodés J. Fulminant hepatic failure. Lancet 1997; 349: 1081–85. Khuroo MS, Teli MR, Skidmore S, Sofi Ma, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981; 70: 252–55. Tsega E, Hansson BG, Krawczynski K, Nordenfelt E. Acute sporadic viral hepatitis in Ethiopia: causes, risk factors, an effect on pregnancy. Clin Infect Dis 1992; 14: 961–65. Verschuuren EAM, Haagsma EB, Zijlstra JG, Stegeman CA. Non-oliguric acute renal failure associated with hepatitis E. Nephrol Dial Transpl 1997; 12: 799–801. Verschuuren EAM, Haagsma EB, Zijlstra JG. Fulminant leverfalen door hepatitis E en de indicatie voor levertransplantatie. Intensive Care Rev 1996; 11: 109–12.
EMEA and third-generation oral contraceptives SIR—Jan P Vandenbroucke and Frits R Rosendaal (April 19, p 1113)1 refer to the cross-sectional study by Rosing et al2 which reported an association between the use of oral contraceptives (OCs) and functional resistance to the natural anticoagulant, activated protein C (APC); they found greater APC resistance among women using “third generation” OCs than among those who used second-generation OCs. According to Vandenbroucke and Rosendaal, those results “fit admirably with the epidemiological data”, showing that the incidence of deepvenous thrombosis and pulmonary embolism (VTE) is about twice as high in users of third-generation OCs as in second-generation OC users. They wonder why the results of the epidemiological studies have apparently been ignored by the European Agency for the Evaluation of Medicinal Products (EMEA); they suggest that EMEA experts have focused on irrelevant arguments made redundant by further analyses; and they seek the involvement of “independent consumer boards or patient platforms in drugsafety regulation” who might be able to resist pressure better.
290
The comparative safety of secondgeneration and third-generation OCs was addressed by the scientific committee of EMEA (the CPMP) in October, 1995, and again, after the publication of the first four epidemiological studies, in December, 1995, and in January, 1996. CPMP set up a working group (including experts in pharmacoepidemiology, clinical pharmacology, obstetrics and gynaecology, cardiology, haemostasis, and biostatistics) which continues to hold regular meetings to analyse all new data. CPMP’s evaluation of the epidemiological evidence was set out on Jan 22, 1997. At that time, seven studies had been presented to CPMP. The risk of VTE was higher in women who used desogestrel or gestodene containing OCs (third generation) than in women using OCs containing levonorgestrel (the majority), lynoestrol, or norethisterone. The increased risk was about two-fold in the first four studies (and significant in three). In the next three studies, the risk difference was less; one was reported as an interim analysis,3 one reached statistical significance,4 and the other did not.5 Because of possible confounding biases, CPMP asked for further data and analyses from the investigators and from the marketing authorisation holders. However, not all the relevant information was available to the investigators so the impact of bias and confounding could not be fully evaluated. Nonetheless, the difference in risk decreased with increasing control for factors that could constitute confounders and introduce bias. The apparent absolute increase in risk of VTE is low even in third-generation OC users, and the case fatality rate is also low. The emergence of a new possible biological explanation (ie, decreased APC sensitivity) in no way permits “immediate separation of epidemiological chaff from wheat”. A mechanism for an association between a medicinal product and a risk strengthens the probability of a causal relation but does not prove it. The new method for measuring thrombin formation needs further validation and a more analytical approach than a cross-sectional study. The risk of VTE is linked to the balance between activation of the coagulation system and the fibrinolytic system, so simultaneous measurement of fibrinolytic activity is needed. One such study planned, at CPMP’s initiative, will include measurement of APC resistance (by the current method and by Rosing’s new method) at the same time in the menstrual cycle. The study will be done by the three manufacturers of third-generation OCs.
An assessment of the risks and benefits of OCs must take into account arterial complications such as myocardial infarction and stroke. Third-generation OCs might have an advantage here. CPMP has asked investigators to pool the WHO and the Transnational Study data to achieve better statistical power. In general, it would be valuable to know more about what risks patients are willing to take to attain certain benefits, once these have been reasonably well established. However, the regulatory process would probably benefit more from such knowledge than from direct involvement of “consumer boards”. CPMP and its ad hoc group will continue to assess the data and will recommend such regulatory measures as may be necessary. *J M Alexandre, K Strandberg *CPMP, EMEA, 7 Westferry Circus, London E14 4HB, UK; and Ad hoc Expert Group on Third Generation Oral Contraceptives and Cardiovascular Risks, CPMP
1
2
3
4
5
Vandenbroucke JP, Rosendaal FR. End of the line for “third-generation-pill” controversy? Lancet 1997; 349: 1113–14. Rosing J, Tans G, Nicolaus GA, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and thirdgeneration oral contraceptives. Br J Haematol 1997; 97: 233–38. Lidegaard O. Oral contraceptives and venous thromboembolism: an epidemiological review. Eur J Contracept Reprod Health Care 1996; 1: 13–20. Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Populationbased study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–88. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995; 15: 195–200.
Home blood-pressure control in Japanese hypertensive population SIR—Giuseppe Mancia and colleagues (Feb 15, p 454)1 suggest that among the Italian hypertensive population, the number of patients with inadequate blood-pressure control is high not only when assessed in the clinic but also when assessed at home. We have investigated blood-pressure control at home among hypertensive patients living in Kahoku, a rural Japanese town.2 Our study comprised 2582 adults (1017 aged 25–64 years, 1565 aged ⭓65 years), which was 52% of the eligible adult population of Kahoku. We defined home blood pressure as the mean value of 20 home measurements
Vol 350 • July 26, 1997