Prolonged and increased postoperative risk of venous thromboembolism: rationale for even more ‘extended’ prophylaxis?

Abstract

Evaluation of: Sweetland S, Green J, Liu B et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 339, b4583 (2009).

It is well known that the risk of venous thromboembolism is increased after surgery; however, specific data on how long this risk lasts or how the risk varies by type of surgery is limited. The Million Women Study is a population-based prospective study that recruited 1.3 million women through the National Health Service breast screening program. This study used data from the Million Women Study to examine the magnitude and the duration of the risk of venous thromboembolism after different types of surgery with a mean follow-up duration of 6.2 years. The risk was found to be higher and longer lasting than previously thought, with considerable variation among different types of surgery; therefore, raising important questions regarding the optimal duration of prophylaxis.

Keywords::

• postoperative prophylaxis
• surgery
• venous thromboembolism

The Million Women Study is a population-based prospective study that recruited 1.3 million women through the National Health Service (NHS) breast screening program between 1996 and 2001. The current study used data from the Million Women Study and electronically linked it to the inpatient and day-case hospital admission records in central NHS databases [1]. The exposure of interest was an inpatient or day-case hospital admission, for a surgical procedure. The main outcomes were the first diagnosis of pulmonary embolism or deep vein thrombosis as an inpatient or day-case hospital admission or as an underlying condition. Exclusion criteria included patients who had been admitted for venous thromboembolism (VTE) prior to recruitment or those with a history of blood clots, clotting problems or previous cancer. To minimize the confounding effect of multiple operations, women who had more than one surgery procedure were also excluded.

Results

In total, 947,454 women were included in the main analyses, and participants were followed for a total of 5.84 million person years (mean 6.2 years per woman), during which time 239,614 women (25%) had an operation. Baseline characteristics were generally similar between women who had an operation and those who did not, except that women who had an operation after recruitment were slightly more likely to have been current users of hormone-replacement therapy. During follow-up, 5419 women were admitted to hospital with pulmonary embolism or deep vein thrombosis and 270 had a first diagnosis of VTE at death.

The relative risk of VTE after surgery was significantly elevated compared with incidence rates without surgery. Women were 40-times more likely to develop VTE during the first week after an inpatient operation (relative risk: 40.3; 95% CI: 30.7–52.8). The risk peaked at 110 (95% CI: 112.5; 95.3–132.8) times more likely during the third postoperative week, after which the risk started to decline but remained substantially elevated up to 12 weeks postoperation. The overall relative risk was 3.7 (95% CI: 2–4.9) 10–12 months postoperatively. After day-case surgery, the relative risks of VTE were lower than after inpatient surgery but still significantly increased.

In the 6 weeks after inpatient surgery, the greatest relative risk was that associated with joint replacement, at more than 200-times the risk without surgery (relative risk: 220.6; 95% CI: 187.8–259.2). However, this risk decreased rapidly 7–12 weeks postsurgery to 39.7 (95% CI: 27.3–57.8).

The highest relative risk for postoperative weeks 7–12 was after inpatient surgery for cancer (53.4; 95% CI: 40.0–71.4). Inpatient cancer surgeries continued to be associated with elevated risk 4–12 months after surgery (34.4; 95% CI: 29.3–40.2) and even up to 1 year or more after surgery (6.1; 95% CI: 4.9–7.6). The overall relative risk after inpatient surgery for noncancer conditions was 3.3 (95% CI: 2.8–3.9) 4–12 months after surgery and 1.7 (95% CI: 1.5–1.9) 1 year or more after surgery.

The incidence rate for VTE without surgery was 0.7 per 1000 person-years, which is equivalent to 0.058 per 1000 person-months. The corresponding standardized incidence rates were 2.6, 0.4, and 0.1 per 1000 person-months at 12 weeks, 4–12 months and 1 year after inpatient surgery, respectively. For comparison, the rates for day-case surgery with 0.4, 0.2 and 0.09 per 1000 person-months, respectively.

Expert commentary & five-year view

It is well known that the risk of VTE is increased after surgery; however, specific data on how long this risk lasts or how the risk varies by type of surgery is limited because of the paucity of studies examining this relationship [2]. This is the only study where the large sample size permits detailed profiling of magnitude and duration of increased risk over time since surgery and categorization of the risk by different types of surgery. The highest risk for VTE was observed during the first 6 weeks after inpatient surgery, reaching a peak in the third postoperative week. The risk declined afterwards but continued to be significantly elevated for up to 12 weeks from orthopedic surgery and up to 1 year from cancer surgery. These new data suggest that the magnitude of VTE risk after surgery is greater and longer lasting than previously thought. No data regarding the prophylaxis regimens were included in the study; however, it is likely that most women in this study received some form of prophylaxis. This implies that the actual magnitude of thromboembolic risk after surgery could have been even higher, especially during the first few weeks when such prophylaxis was most likely to have been administered.

The optimal duration for postoperative VTE prophylaxis after orthopedic surgery is unknown; however, there is strong evidence from physiological, radiological and epidemiological studies that the risk extends well beyond the period of hospitalization [3]. The current American College of Chest Physicians (ACCP) guidelines recommend extending prophylaxis beyond 10 days and up to 35 days for patients undergoing total hip replacement, total knee replacement and hip fracture surgery [4]. The recent NICE guidelines recommend extended duration of prophylaxis beyond hospital discharge after hip replacement and surgery for hip fracture for up to 4 weeks [5]. Results from this study show persistence of elevated risk after joint replacement and fracture surgery for up to 12 weeks postoperatively. These findings support those from the large Norwegian Arthroplasty Register study that showed higher mortality for 3 months after hip replacement (over a third of deaths were caused by VTE) [6]. This new data calls for more clinical trials to determine the optimal duration of extended prophylaxis to prevent morbidity and mortality associated with postoperative VTE [7]. Such studies should examine whether the benefit of extending prophylaxis beyond 35 days after joint replacement and fracture surgery will outweigh the resulting bleeding risks and the involved costs.

For patients undergoing cancer surgery, the elevated relative risk of VTE continued up to 1 year after surgery, probably owing to the effect of the underlying cancer, per se, rather than a long-lasting effect of the surgery peformed. The current ACCP guidelines recommend continuing thromboprophylaxis after hospital discharge with low-molecular-weight heparin for up to 28 days in general surgery and gynecologic surgery patients undergoing major cancer surgery [4]. The American Society of clinical oncology recommends continuing prophylaxis for at least 7–10 days postoperatively and considering prolonged prophylaxis for up to 4 weeks in patients undergoing major abdominal or pelvic cancer surgery for high-risk features, such as residual malignant disease after operation, obese patients, and those with a previous history of VTE [8]. A meta-analysis of three randomized controlled trials comparing extended (4 weeks) with limited prophylaxis concluded that there is limited and low-quality evidence that extended duration low-molecular-weight heparin for perioperative thromboprophylaxis reduces VTE in patients with cancer undergoing major abdominal or pelvic surgery. More and better-quality evidence is needed to justify extended regimens [9]. Results from the current study that show persistent risk for up to 1 year postoperatively also call for trials to examine whether extending prophylaxis beyond 28 days would be beneficial to patients undergoing cancer surgeries.

Recently, two new oral anticoagulants, dabigatran etixalate (a direct thrombin inhibitor) and rivaroxaban (a Factor Xa inhibitor) have been approved for VTE prophylaxis after orthopedic surgery in the EU and Canada [10]. These new agents offer the convenience of oral administration along with the advantage of the lack of need for monitoring [11,12]. These factors will give these new agents a significant advantage if prolonged prophylaxis proves to be necessary and could help both physicians and patients to adhere to optimal preventive strategies[7]. In light of this study’s findings, strong consideration must be given to these new agents in clinical trials involving more extended prophylaxis beyond what is currently recommended. Obviously, more data on the cost–effectiveness of these agents and on their long-term safety profile will also need to be considered before making any broad recommendations on their wide use for ‘extended’ prophylaxis.

Key issues

• • This large prospective study provided a detailed profile of postoperative venous thromboembolism risk in women that proved to be higher and longer lasting than previously thought.

• • The risks of venous thromboembolism were greatest after joint replacement and cancer surgery.

• • The higher magnitude and longer duration of this risk call for more trials to define the optimal duration of ‘extended’ prophylaxis, especially after joint replacement and cancer surgeries.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.