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Evidence-based Breast Cancer Treatment Guidance - The State of the Art

Compiled by:
Constantine Kaniklidis, medical researcher, European Association for Cancer Research (EACR)

[ Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]



Interim Report on the Early Termination of the LIFT Tibolone Study [updated: 12/16/06]

§ LIFT Study Early Termination: Analysis

  • LIFT Tibolone Study Halted: Increased Risk of Stroke
    Evidencewatch
    reports an early termination of the Organon LIFT study investigating tibolone efficacy on new vertebral fractures in elderly osteoporotic women under DSMB and Steering Committee rules. The interim findings reported an increased incidence of ischemic plus hemorrhagic events (strokes) in tibolone treatment group compared to the control group.

    The precise and full clinical implications however are not wholly clear:


    1. The study population was elderly osteoporotic women with a high risk of fracture, with the average age at baseline (study entry - recruitment began in 2001, and recruitment completed June 2003) of 68. Yet the vast majority of tibolone users average 10 years younger given typical deployment for vasomotor (climacteric) hot flashes. Indeed, Evidencewatch notes that Organon scientists determined in 2004 that at least in the UK, tibolone was preferentially prescribed to women with an increased risk for breast and endometrial cancer (Wierik et al. Climacteric (2004): Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study).

    2. The Organon Tibolone Clinical Study Database, comprised of more than 6500 women-years of tibolone use in women who are on average much younger than the elderly osteoporotic women included in the LIFT study, fails to suggest any significant increased risk of stroke.

    3. The study dose used in the LIFT study was 1.25 mg./daily, and indeed 1.25 mg also (as compared with 2.5 mg/daily) significantly decreases hot flashes, although the higher 2.5 mg tibolone dose is both faster in onset of action and with higher reductions in hot flash frequency and severity. However, it is important to note that the clinical trial database does not suggest that in younger postmenopausal women treated with either dose of tibolone, 2.5 mg nor 1.25 mg, there is any increased risk on stroke.

    4. It appears that the parameter with the most impact in the LIFT study's outcome regarding stroke is age, although this is also true for the placebo group. The fact that NO increases in incidence of VTE (venous thromboembolism) nor MI (myocardial infarction) are found with tibolone makes it more difficult to explain the mechanism by which tibolone increases the risk on stroke in these elderly women (I am indebted to Dr. Mirjam Mol-Arts, Livial Global Venture Teamleader and head of clinical projects in HRT at Organon, manufacturer of tibolone (Livial), for this clarification).

      Indeed, Evidencewatch notes that in our own research, some studies have found tibolone (2.5 mg/daily) to be safe in postmenopausal patients with high risk factors in their history such as thromboembolic disorders, diabetes mellitus, hypertension, cardiovascular disease, pulmonary embolism, and stroke (see F. Szanto, Tibolone therapy in postmenopausal women with a history of many risk factors) over a 36-month period, a finding hard to reconcile with the LIFT results.

    5. Against the thrust of the LIFT study findings on stroke, tibolone as a six-month course (at 2.5 mg/daily) in postmenopausal women was found to counteract the increase of the intima media thickness (IMT) of the common carotid arteries (CCA), as determined by Anedda et al. (Hormone Res (2004): Observational Study on the Efficacy of Tibolone in Counteracting Early Carotid Atherosclerotic Lesions in Postmenopausal Women) and also by Erenus et al. (Fertil Steril (2002): Effect of tibolone treatment on intima-media thickness and the resistive indices of the carotid arteries), and this suggests an anti-atherosclerotic effect by tibolone, as it is well-established that increased CCA-IMT values are associated with a higher risk of long-term stroke recurrence (Tsivgoulis et al., Stroke (2006): Common Carotid Artery Intima-Media Thickness and the Risk of Stroke Recurrence). [Tibolone's effect on CRP (C-reactive protein), also a risk factor for stroke, is not wholly clear, as there have been inconsistent findings across studies.]

§ Some Guidance on Stroke Risk Reduction

Evidencewatch continues to investigate this issue and will post additional guidance as appropriate, but pending that advises that women currently using tibolone explore this matter candidly with their physicians. Evidencewatch advises, however, for any women who elects to continue tibolone therapy that at the very least some basic proactive stroke-preventive measures be taken:

 

Copyright © 2006. Constantine Kaniklidis