Re: Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
Although the large number of cases of VTE (10,562) and linkage to details of co-morbid conditions and BMI allowing adjustment for many important confounders are major strengths of the analysis by Vinogradova and colleagues, it is unlikely that these adjustments completely corrected for the core problem with database and case-control studies; healthy user effect and preferential prescription of low androgen progestogens to women at higher risk of VTE [1, 2]. It is of interest that in the duration of use analysis, a significantly increased risk for new users and restarters was seen only for levonorgestrel products. One likely explanation is that providers have responded to negative publicity concerning low-androgen progestogens by switching patients to levonorgestrel (LNG) pills, increasing the high risk pool among LNG users.
Preferential prescribing of newer low dose/low androgen products to high risk women is also the likely explanation for the findings seen with respect to estrogen dose. Farmer initially pointed out the “inverse-dose response” for ethinyl estradiol (EE) and VTE risk during the first pill scare in the 1990s [3]. Similar results are observed in the Vinogradova paper. I calculated the crude OR for VTE (relative to LNG) for 20 mcg EE norethisterone at 1.25 (0.95, 1.64), while for 30/40 mcg the OR is 1.02 (0.82, 1.27). For 20 mcg gestodene the OR is 2.24 (1.46, 3.44) while for 30 mcg the OR is reduced at 1.46 (1.18, 1.80). Only with the desogestrel preparations was the risk marginally higher with 30/40 mcg EE (OR 1.87 (1.54, 2.25) than for 20 mcg (1.71 (1.34, 2.17). Data for 20 and 30 mcg drospirenone was not provided. This provides strong evidence that the observed differential effect of progestogen type observed by Vinogradova and colleagues also reflects preferential prescribing of newer low androgen pills to high risk women.
References
[1] Rowlands S, Devalia H, Lawrenson R. Preferential prescribing of type of combined oral contraceptive pill by general practitioners to teenagers with acne. Eur J Contracept Reprod Health Care. 2001;6:9-13.
[2] Heinemann LA, Lewis MA, Assmann A, Gravens L, Guggenmoos-Holzmann I, Working Group for Pharmacoepidemiology B-B. Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives? Pharmacoepidemiol Drug Saf. 1996;5:285-94.
[3] Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany. American journal of obstetrics and gynecology. 1998;179:S78-86.
Competing interests:
I have received payments for consulting from Agile Pharmaceuticals, Abbvie Pharmaceuticals, Bayer Healthcare, ContraMed, Evofem Inc, HRA Pharma, Merck Pharmaceuticals, Microchips, Teva Pharmaceuticals and the Population Council. I have also received research funding from Abbvie, Bayer, the Population Council, and the Bill & Melinda Gates Foundation. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by my employer, OHSU.
29 June 2015
Jeffrey T. Jensen
Professor, and Vice Chair Research, Department of Obstetrics & Gynecology
Oregon Health & Science University
mail code UHN-70, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239
Rapid Response:
Re: Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
Although the large number of cases of VTE (10,562) and linkage to details of co-morbid conditions and BMI allowing adjustment for many important confounders are major strengths of the analysis by Vinogradova and colleagues, it is unlikely that these adjustments completely corrected for the core problem with database and case-control studies; healthy user effect and preferential prescription of low androgen progestogens to women at higher risk of VTE [1, 2]. It is of interest that in the duration of use analysis, a significantly increased risk for new users and restarters was seen only for levonorgestrel products. One likely explanation is that providers have responded to negative publicity concerning low-androgen progestogens by switching patients to levonorgestrel (LNG) pills, increasing the high risk pool among LNG users.
Preferential prescribing of newer low dose/low androgen products to high risk women is also the likely explanation for the findings seen with respect to estrogen dose. Farmer initially pointed out the “inverse-dose response” for ethinyl estradiol (EE) and VTE risk during the first pill scare in the 1990s [3]. Similar results are observed in the Vinogradova paper. I calculated the crude OR for VTE (relative to LNG) for 20 mcg EE norethisterone at 1.25 (0.95, 1.64), while for 30/40 mcg the OR is 1.02 (0.82, 1.27). For 20 mcg gestodene the OR is 2.24 (1.46, 3.44) while for 30 mcg the OR is reduced at 1.46 (1.18, 1.80). Only with the desogestrel preparations was the risk marginally higher with 30/40 mcg EE (OR 1.87 (1.54, 2.25) than for 20 mcg (1.71 (1.34, 2.17). Data for 20 and 30 mcg drospirenone was not provided. This provides strong evidence that the observed differential effect of progestogen type observed by Vinogradova and colleagues also reflects preferential prescribing of newer low androgen pills to high risk women.
References
[1] Rowlands S, Devalia H, Lawrenson R. Preferential prescribing of type of combined oral contraceptive pill by general practitioners to teenagers with acne. Eur J Contracept Reprod Health Care. 2001;6:9-13.
[2] Heinemann LA, Lewis MA, Assmann A, Gravens L, Guggenmoos-Holzmann I, Working Group for Pharmacoepidemiology B-B. Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives? Pharmacoepidemiol Drug Saf. 1996;5:285-94.
[3] Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany. American journal of obstetrics and gynecology. 1998;179:S78-86.
Competing interests: I have received payments for consulting from Agile Pharmaceuticals, Abbvie Pharmaceuticals, Bayer Healthcare, ContraMed, Evofem Inc, HRA Pharma, Merck Pharmaceuticals, Microchips, Teva Pharmaceuticals and the Population Council. I have also received research funding from Abbvie, Bayer, the Population Council, and the Bill & Melinda Gates Foundation. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by my employer, OHSU.