Effects of Aromatase Inhibitors and Tamoxifen on Coagulation Factors

Tamoxifen, long considered the gold standard for treating estrogen-receptor (ER) positive, early-stage breast cancer, is known to increase the risk of thrombotic events (blood clots). This is of particular concern for women who have clotting disorders. Investigations have been ongoing to determine if aromatase inhibitors (AIs), also approved for treating postmenopausal women with ER-positive tumors, similarly increase a patient’s risk for thrombotic events. Data from various studies suggest that although AIs may increase the incidence of thrombotic events in cancer patients, the risk is not as great as it is with tamoxifen.

Researchers in Edinburgh, Scotland, conducted an open, randomized, pharmacodynamic study to determine whether different AIs affected individual blood coagulation factors differently. They also wanted to find out how switching from an AI to tamoxifen might further affect blood coagulation. Investigators recruited 120 postmenopausal women with invasive ER+ breast cancer, described as “otherwise healthy,” and randomized them to receive 16 weeks of adjuvant therapy with either letrozole (Femara), anastrozole (Arimidex), or exemestane (Aromasin). Following the initial 16-week treatment period, all the patients were switched to tamoxifen.

The women’s fasting blood levels were obtained at baseline and re-measured following 12 and then 16 weeks of treatment. Final fasting blood level measures were obtained after 8 months of tamoxifen therapy. Specific coagulation factors analyzed included plasminogen activator inhibitor antigen, von Willenbrand’s Factor (vWF) antigen, antithrombin III (ATIII), protein C, protein S total, protein S free, activated protein C, resistance (APCR), factor VIII, and fibrinogen.

At the outset of the trial, the researchers hypothesized that because AIs reduce the level of circulating estrogens, their effect on coagulation would be either positive or negligible. Instead they found that the AIs did affect coagulation factors, but not all of the AIs affected every factor in the same manner. Results were evaluated using covariate analysis. Researchers determined the following:

● Only minor changes were seen in any coagulation factors for patients who received the non-steroidal AIs anastrozole or letrozole.

● Exemestane, the only steroidal AI, significantly reduced levels of the anticoagulants protein C and ATIII, which investigators suggested might predispose patients to an increased risk of thromboembolic disease.

● The non-steroidal AIs produced a significant increase in vWF from baseline, but the mean percentage change did not differ significantly from that seen with exemestane.

● The effects of tamoxifen on coagulant levels were significant and complex; tamoxifen significantly decreased levels of protein C and the anticoagulant ATIII, which investigators theorized might “explain the increased risk of deep vein thrombosis observed with this drug.” The agent also caused a significant increase in protein S free.

The authors concluded that AIs and tamoxifen have different but significant effects on coagulation that might account for their association with an increased risk of thrombosis. The more significant effect of tamoxifen on certain coagulation factors might account for its stronger association with thrombotic events.