Thromboembolism incidence

Laboratory tests. They show data for haemoconcentration with high haematocritis values, polyglobulism and multiple thromboembolic incidents. 

Celecoxib, which has a low selectivity for COX-2 compared to COX-1, is still available, although its more selective successor, valdecoxib has been withdrawn. Etoricoxib, the successor to rofecoxib, is marketed in Europe but not in the USA. In a large multinational clinical trial, etoricoxib caused no more thromboembolic events than diclofenac, but after 18 months the incidence of gastrointestinal ulcers and bleeding was the same for both drugs [4]. 

COX-2 synthesises PGI2 (prostacyclin) and the high incidence of myocardial infarctions with selective COX-2 inhibitors has been attributed to inhibition of COX-2 in vascular tissues. Prostacyclin, made by blood vessel walls, inhibits aggregation of platelets and maintains a balance with thromboxane. Thromboxane, which is released by platelets, promotes clotting. Prostacyclin is synthesised mostly by COX-1, but in humans selective COX-2 inhibition reduces its biosynthesis in vivo. This reduced synthesis may lead to an overactive thromboxane system and increased risk of thromboembolism. 

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... 

HRT on the incidence of venous thromboembolism, breast cancer, or CHD. Lower-dose HRT provides women with an alternative to standard-dose HRT for menopausal symptoms but also should be recommended only for a short duration. Although many women have switched to lower-dose HRT,... 

CHD is the leading cause of death among women in the United States. Retrospective data indicated that HRT was associated with a decrease in risk of CHD by 30% to 50%.21 However, the results of recent RCTs demonstrate that HRT does not prevent or treat CHD in women and that it actually may cause an increase in CHD events. The HERS, published in 1998, was the first RCT conducted in women with established CHD. This trial demonstrated an increased incidence of CHD events within the first year of treatment with HRT and an increased risk of venous thromboembolism (VTE) and gallbladder disease. There was a trend of decreasing incidence... 

Adverse effects include nausea, weight gain, breast tenderness, and breakthrough bleeding. Oral contraceptives have also been associated with an increased incidence of thromboembolic disease, particularly in women who use tobacco products or have other risk factors for thromboembolism. The development of these complications is significantly reduced when low-dose estrogen formulations of oral contraceptives are used.3... 

Aspirin is maximally effective as an antithrombotic agent at the comparatively low dose of 81 to 325 mg per day. (The antipyretic dose of aspirin in adults is 325 to 650 mg every 4 h.) Higher doses of aspirin are actually contraindicated in patients prone to thromboembolism. At higher doses, aspirin also reduces synthesis of prostacyclin, another arachidonic acid metabolite. Prostacyclin normally inhibits platelet aggregation. The prophylactic administration of low-dose aspirin has been shown to increase survival following myocardial infarction, decrease incidence of stroke, and assist in maintenance of patency of coronary bypass grafts. 

However, the mechanism for the increased incidence of cardiovascular disease in CHC users is believed to be thromboembolic and thrombotic changes, not atherosclerosis. 

The package insert provides preliminary data indicating a higher incidence of thromboembolic events with the patch. The benefits of increased compliance must be weighed against the risk of increased estrogen exposure and possibly more thromboembolic events. 

Tamoxifen users present also a doubling incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) (118 vs. 62 cases). This increase is similar to that seen with HRT. There are some aspects of this side effect that should be commented on to improve the management of women eligible for tamoxifen treatment and at risk for DVT (Goldhaber 2005). In the subanalysis of the Italian study (Decensi et al. 2005), the venous thromboembolism definition included DVT, PE, and superficial phlebitis. Most of the VTE that the authors reported were, in fact, cases of superficial phlebitis, whereas the admitted definition of venous thromboembolism excludes this entity. Such conceptual differences, together with differences in age and background characteristics between the four studies, can explain the diversity in the incidences observed. 

Middeldorp, S., et al., "A Prospective Study of Asymptomatic Carriers of the Factor V Leiden Mutation to Determine the Incidence of Venous Thromboembolism," Ann. Intern. Med., 135, 322-327 (2001). 

However, soon after licensing, an increased incidence of venous thromboembolism (VTE) was suspected. By 1990-1 there were three main sources of information that could have been regarded as possibly generating h)rpotheses. 

There have been an increased number of incidences of endometrial changes, thromboembolic events, and uterine malignancies while using tamoxifen. 

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

The increased risk of thromboembolism associated with atrial fibrillation and with the placement of mechanical heart valves has long been recognized. Similarly, prolonged bed rest, high-risk surgical procedures, and the presence of cancer are clearly associated with an increased incidence of deep venous thrombosis and embolism. Antiphospholipid antibody syndrome is another important acquired risk factor. Drugs may function as synergistic risk factors in concert with inherited risk factors. 

Of 8028 postmenopausal women with receptor-positive early breast cancer who were randomly assigned doubleblind to letrozole, tamoxifen, or a sequence of these agents for 5 years, 7963 were included in an analysis of cardiovascular events over a median follow-up time of 30 months (8). There was a similar overall incidence of cardiac adverse events (letrozole 4.8% tamoxifen4.7%), but more grade 3-5 events with letrozole (2.4% versus 1.4%), an excess that was only partly attributable to prior hypercholesterolemia. There were more thromboembolic events with tamoxifen (3.9% versus 1.7% overall and 2.3% versus 0.9% for grade 3-5 events). There were no significant differences between tamoxifen and letrozole in the incidence of hypertension or cerebrovascular events. 

Fosfestrol is an unusual agent used in Japan for the treatment of prostatic carcinoma but not accepted by experts in Europe. Described as an estrogen, in European studies it had a high incidence of complications, including fluid retention (16%), myocardial infarction (10%), and thromboembolism (6.3%). A case of adrenocortical insufficiency has now been documented in Japan, involving a 59-year-old man who had taken the drug for 10 years (3). 

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). 

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