Venous thromboembolism, oral

Patients with cancer who develop a venous thromboembolism may benefit from long-term therapy with a low molecular weight heparin (at least the first 3-6 mo of pharmacotherapy) instead of oral warfarin... 

FIGURE 7-5. Treatment approach for patients with VTE. INR, International Normalized Ratio IV, intravenous LMWH, low-molecular-weight heparin PO, oral SC, subcutaneous UFH, unfractionated heparin VTE, venous thromboembolism. (Adapted from Nutescu EA. Emerging options in the treatment of venous thromboembolism. Am J Health Syst Pharm 2004 61 (Suppl 7) S16, with permission.)... 

Many systemically administered estrogen products are available in the United States, but conjugated equine estrogens (CEEs), prepared from the urine of pregnant mares, is the most widely prescribed. Transdermal estrogen preparations are also available and usually are prescribed for patients who experience adverse effects, elevated triglycerides, or liver function abnormalities while taking an oral product. Transdermal preparations also have a lower incidence of venous thromboembolism than oral preparations.9... 

Adverse effects of estrogen include nausea, headache, breast tenderness, and heavy bleeding. More serious adverse effects include increased risk for coronary heart disease, stroke, venous thromboembolism, breast cancer, and gallbladder disease. Transdermal estrogen is less likely than oral estrogen to cause nausea, headache, breast tenderness, gallbladder disease, and deep vein thrombosis. 

Spannagl, M., et al., "Are Factor V Leiden Carriers Who Use Oral Contraceptives at Extreme Risk for Venous Thromboembolism " Eur. ]. Contracept. Reprod. Hlth. Care, 5, 105-112 (2000). 

Cilest contains ethinylestradiol and norgestimate whereas Yasmin contains ethinylestradiol in combination with drospirenone. Both are combined oral contraceptives available as tablets, which have to be taken once daily for 21 days. Both are contraindicated in patients with venous thromboembolic diseases. 

Scarabin PY, Oger E, Plu-Bureau GEStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003 362(9382) 428-32. 

The Medicines Commission of the UK has reviewed all currently available relevant data and has confirmed that the incidence of venous thromboembolism is about 25 per 100 000 women per year of use (21). The incidence of venous thrombembolism in users of second-generation combined oral contraceptives is about 15 per 100 000 women per year of use. This indicates a small excess risk... 

The incidence of venous thromboembolic disease in about 540 000 women born between 1941 and 1981 and taking oral contraceptives was 4.1-4.2 cases per 10 000 woman-years (22). 

Cyproterone acetate in combination with ethinylestra-diol is indicated for the treatment of women with severe acne and moderately severe hirsutism. This product has been associated with a greater risk of venous thromboembolism than oral contraceptives. However, in a rigorous case-control study the risk of venous thromboembolism with cyproterone acetate + ethinylestradiol was not significantly greater than the risk in women who took conventional oral contraceptives (25). 

Despite the variations that are found, the overall conclusion is that oral contraceptives cause an increase in coagulation factors I (fibrinogen), II, VII, IX, X, and XII, and a reduction in antithrombin III concentrations, which would be expected to predispose to venous thromboembolism, especially if not counterbalanced by an increase either in fibrinolytic activity or of other inhibitory proteins of the coagulation, such as protein C (70). 

England that the Committee on Safety of Medicines had written to prescribers in 1995 stating that three unpublished studies on the safety of combined oral contraceptives in relation to venous thromboembolism had indicated about a two-fold increase in the risk of such conditions compared with the preceding generation of products. This issue of a two-fold increase became crucial to the case. For reasons of causation, as the Judge put it, the claimants had accepted the burden of proving that the increase in risk was not less than two-fold. 

Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease the findings from database studies in the United Kingdom and Germany. Am J Obstet Gynecol 1998 179(3 Pt 2) S78-86. 

Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991 133(l) 32-7. 

Machin SJ, Mackie IJ, Guillebaud J. Factor V Leiden mutation, venous thromboembolism and combined oral contraceptive usage. Br J Fam Planning 1995 21 13-4. 

Badaracco MA, Vessey MP. Recurrence of venous thromboembolic disease and use of oral contraceptives. BMJ 1974 1(901) 215—7. 

Herings RM, Urquhart J, Leufkens HG. Venous thromboembolism among new users of different oral contraceptives. Lancet 1999 354(9173) 127-8. 

Jick H, Kaye JA, Vasilakis-Scaramozza C, Jick SS. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995 cohort and case-control analysis. BMJ 2000 321(7270) 1190-5. 

Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism a five-year national case-control study. Contraception 2002 65(3) 187-96. 

Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous thromboembolism in relation to oral contraceptive use. Obstet Gynecol 1987 69(l) 91-5. 

There is other evidence that transdermal estrogen replacement therapy has relatively little effect on hemostasis. In a case control study, 155 consecutive patients with a first documented episode of idiopathic venous thromboembolism, 92 of whom had had a pulmonary embolism and 63 a deep venous thrombosis, were compared with 381 healthy matched controls (88). Overall, 32 (21%) of the cases and 27 (7%) of the controls were current users of oral estrogen replacement therapy, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal estrogen replacement therapy. After adjustment for potential confounding variables, the odds ratios for venous thromboembolism in current users of oral and transdermal estrogen replacement therapy compared with non-users were 3.5 (95% Cl = 1.8, 6.8) and 0.9 (0.5, 1.6) respectively. Estimated risk for venous thromboembolism in current users of oral estrogen replacement therapy compared with transdermal users was 4.0 (1.9, 8.3). 

In a case-control study 155 postmenopausal women who had had venous thromboembolism were compared with 381 matched controls (91). In all, 32 cases and 27 controls were current users of oral replacement therapy, whereas 30 cases and 93 controls were current users of transdermal products. After adjustment for potential confounding variables, the estimated risk ratio for venous thromboembolism in current users of the oral products compared with the transdermal users was 4.0 (1.9-8.3). This is strong evidence that the transdermal route was considerably safer. However, the conclusions of different studies continue to conflict with one another, no doubt in part because of variations in the formulations and patterns of use of the products. 

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