Peri-Operative Hormones: How Should We Manage Them?

Sondra Vazirani, M.D., M.P.H.

Most post-surgical patients are at increased risk for developing deep venous thromboses (DVT) and pulmonary emboli (PE). It is known that both oral contraceptive pills and hormone replacement therapy increase the risk of thromboembolic events. When we have patients taking hormone therapy who are electively scheduled for surgical procedures, should we stop their hormones? If so, when? What kind of DVT prophylaxis should be utilized?

Venous thromboembolic (VTE) events cause increases in morbidity and mortality. In the general population, VTE occurs in an annual rate of 1 to 4 per 1000 adults.¹ Risk factors for the development of VTE include: age, especially if greater than 40 years; prolonged immobilization; prior VTE; major surgery, especially involving the abdomen, pelvis, and lower extremities; pregnancy; estrogen use; malignancy; and other inherited or acquired hypercoaguable states, such as factor V Leiden and antiphospholipid antibody syndrome. In many patients, multiple risk factors can be present and are cumulative.² The only surgeries that are considered low risk for development of VTE are those surgeries which are minor in nature, usually less than an hour in duration, and on patients less than 40 years of age with no clinical risk factors.² The risk for these individuals is less than 1% for proximal vein thrombosis and less than 0.01% for fatal PE.³ Moderate risk surgeries include major and minor surgeries in patients 40-60 years old; major surgeries in patients less than 40 years old with no additional risk factors; and minor surgery in patients with risk factors. The risk for these individuals is 210% for proximal vein thrombosis and 0.1-0.8% for fatal PE. High-risk surgeries are those in patients greater than 40 years old with major surgeries and risk factors. The risk for these individuals is 10-30% for proximal vein thrombosis and 1-5% for fatal PE. The risk of calf vein thrombosis in this group is 40-80%, but these can be asymptomatic and are associated with a low risk of pulmonary embolism, unless there is extension into the proximal system.³ Surgeries that place patients at highest risk for VTE are orthopedic and neurosurgical.²

Oral contraceptive pills (OCPs) are known risk factors for VTE, with a relative risk of approximately 2-5.⁴ Major predisposing risk factors for VTE events in the setting of OCPs are history of prior events and high-dose estrogen. The risk is felt to be from the estrogen component, rather than the progestin, and is felt to be dose related.⁵ However, it has been reported that the third generation OCPs (containing desogestrel or gestodene as the progestin component) are associated with an up to 4-fold increase in risk of VTE when compared to users of second generation OCPs, especially among young, healthy women.⁶

The attributable postoperative risk of OCPs has been reported 31/10,000 as compared to 8/100,000.⁷ Additionally, the DTB cites two small studies done in the 1970's that implicate OCPs with increased post operative VTE, up to three- and four-fold.⁴ The Physician's Desk Reference (PDR) cites a two- to seven-fold increase in the relative risk of postoperative thromboembolic complications with the use of OCPs. "If feasible, OCPs should be discontinued at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increased risk of thromboembolism, and also during and following prolonged immobilization."⁸

Stopping OCPs prior to surgery may be of concern to primary care doctors and patients if the risk of pregnancy with other utilized methods is high due to improper technique or low success rate. The Thromboembolic Risk Factor (THRIFT) Consensus Group and the Royal College of Obstretricians and Gynaecologists (RCOG) in papers published in the early 90's, recommend continuing OCPs for this reason, and rather to use VTE prophylaxis in the peri-operative period.⁴ An alternative strategy is to switch women to progestin-only pills, as this does not have a high association with VTEs.

HRT has a biological potency one-forth to one-fifth of that of estrogens in OCPs. Despite the lower estrogen profile, HRT, too, is associated with VTE. The PEPI trial in 1995 and three observational studies published in 1996, reported an association with HRT and VTE.^1,9 It was noted that HRT causes a two- to four-fold increase in risk for DVT and PE compared with non-users.

The Heart and Estrogen-Progestin Replacement Study (HERS) study was a landmark study designed to test the effect of HRT on postmenopausal women with coronary artery disease. Additionally, secondary endpoints were specified including evaluation of the incidence of VTE. A letter was written by Grady, et al, in 1997, which was followed by a full report in May 2000. Of note, women with a history of VTE were excluded from the HERS trial. The relative hazard for both DVT and PE were 2.8. The relative hazard in the first 90 days after inpatient surgery was 4.9.¹ An analysis was performed to determine the length of time the risk remains elevated after HRT cessation. The relative hazard remained elevated for at least 30 days, but the number of events were too small to make solid conclusions.¹ The HERS investigators also noted that the risk of VTE was 6-fold for hip fracture, but 18-fold for other lower extremity fractures. This result could have occurred due to lack of power; but the authors propose that DVT prophylaxis is also more aggressively given post hip fracture than compared with other lower extremity fractures. The authors concluded that "women at very high risk because of history of venous thromboembolism, cancer, lower extremity fracture, or immobilization should avoid postmenopausal hormone therapy."¹

As with OCPs, HRT cessation around the time of surgery is controversial. Some manufacturers suggest stopping 4 weeks prior to surgery. This time interval is consistent with the observation in HERS. The THRIFT Consensus Group and RCOG again did not support cessation of HRT, citing insufficient evidence at the time of their reports.⁴ Weighing the pros and cons, the DTB recommends using thromboprophylaxis in the setting of HRT use, rather than cessation.

One concern with cessation of HRT is the recurrence of postmenopausal symptoms. Another concern is the risk of re-institution of the drug. We know from HERS that patients with coronary artery disease had increased coronary events in the first year. Theoretically, reinstitution may cause harm in this manner.

Given the above data, and the fact that VTE risks are cumulative, I recommend stopping OCPs 4 weeks prior to elective, high VTE risk surgery and using an alternative, reliable method of birth control in compliant patients. Options may include a progestin-only pill or condoms plus spermacide. Alternatively, and for low to moderate risk surgeries, OCPs can be continued in the setting of postoperative thromboprophylaxis. Given the effectiveness of low-molecular weight heparins (LMWHs) in high-risk general and orthopedic cases, I would suggest utilizing this agent in addition to early ambulation and pneumatic compression stockings if OCPs are continued. The surgeon may prefer utilizing warfarin over LMWH, and this is also acceptable for high risk general surgery and orthopedic cases. For patients with intracranial neurosurgery where postoperative bleeding is of major concern, pneumatic compression stockings with graded compression elastic stockings can be employed.

It is more difficult to make strong recommendations regarding HRT, as the optimal time period for cessation is not known. Certainly the risk of VTE is increased in HRT users. If the patient can tolerate the symptoms associated with HRT cessation and has no known coronary artery disease, I would stop HRT a minimum of 4 weeks prior to high-risk elective surgery and continue to utilize the VTE prophylaxis of choice for that type of surgery. If HRT is continued up to the time of surgery, VTE prophylaxis is mandated. Given the need for a "wash out" period, I usually will stop HRT solely on a postoperative basis, when continued preoperatively, if prolonged immobility is anticipated (such as with orthopedic cases with no weight bearing for several weeks) or with patients on higher dose estrogen replacement.