Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women
Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial
Elizabeth Barrett-Connor, MD; Deborah Grady, MD; Andreas Sashegyi, PhD; Pamela W. Anderson, MD; David A.  Cox, PhD; Krzysztof Hoszowski, MD; Pentti Rautaharju, MD; Kristine D.  Harper, MD; for the MORE Investigators

Extract from
Discussion

In summary, there was no evidence that raloxifene caused an early increase in risk of CV events, either overall or among postmenopausal women at high risk for or with CHD.  Raloxifene therapy for 4 years did not significantly affect the overall risk of CV events in the total MORE cohort but did significantly reduce the risk of CV events among women at high risk for and among those with established CHD.  Before raloxifene is used for prevention of CV events, these findings must be confirmed by an adequately powered, randomized trial with CV events as predefined outcomes.

Evista belongs to a class of drugs known as selective estrogen receptor  modulators. It attaches to cells in the same way estrogen does, blocking  the hormone's effects on them.

  The drug exerts some of the positive effects of the hormone on the heart and bones, but blocks its impact on breast cancer cells and it does not stimulate the lining of the uterus.

  But new research presented at the European Society of Human Reproduction and Embryology meeting in Lausanne, Switzerland, shows the drug acts differently toward ovarian cancer than it does in breast and in uterine cancer.

  ``In breast and uterine cancer it does not appear to be problem, in ovarian cancer it may stimulate the cells,'' said Paulson.

Two trials versus combined hormone replacement therapy (HRT) showed HRT had a more favourable effect on surrogate end points reflecting the risk of fracture and cardiovascular risk (changes in bone mineral density and lipid profile). Compared with combined HRT, raloxifene reduced the incidence of menorrhagia and mastodynia, but did not relieve symptoms linked to menopause. Results of animal studies call for close clinical monitoring to detect a possible increase in the incidence of ovarian cancer.

Evidence of effectiveness:

Changes in bone mineral density and serum lipids do not necessarily correlate with desired clinical events, therefore trials and data on surrogate outcomes are purposely not included in this letter. For example in one trial fluoride increased bone mineral density and increased the incidence of non-vertebral fractures, and in another trial estrogen/progestin treatment decreased LDL cholesterol and was not associated with a decrease in coronary events.

Raloxifene reduced radiologic vertebral collapse in both the primary (ARR = 2.2%) and secondary prevention (ARR = 6.5%) settings, but had no effect on non-vertebral fractures (including hip fractures). Benefits for reduction in painful vertebral collapse and reduction in early breast cancer were small and of a similar magnitude to the harm of increased thromboembolic events. 

WESTPORT, Sep 27 (Reuters Health) - 

In a very small study comparing the  effect of raloxifene and estrogen on brain metabolism, PET scans demonstrated that raloxifene affects brain metabolism but, unlike estrogen, it does not affect the left frontal cortex, the region associated with cognition and memory.

Dr. Metz said that whether or not raloxifene or estrogen actually cause  behavior and mood changes related to the changes seen on PET is unknown, because none of the women  reported any such changes while taking estrogen, raloxifene or placebo. "This remains theoretical," he  said.

Recent developments in the new endocrinology of selective oestrogen receptor modulators (SERMs) seem to have the potential to transform therapeutics. The emerging data on the multiple effects of raloxifene have generated great excitement that this might be the first multifunctional medicine. Raloxifene was developed for preventing osteoporosis and, like oestrogen, may reduce the risk of cardiovascular disease. In addition, raloxifene may reduce the incidence of breast cancer without increasing that of endometrial cancer.

........but it must be emphasised that neither tamoxifen nor raloxifene ameliorates menopausal symptoms so they are not substitutes for hormone replacement therapy.

......  raloxifene's efficacy as an osteoporosis agent is documented, and proof of multifunctionality must await the results of ongoing trials.

Lilly Barred From Claiming That Evista Lowers  Breast Cancer Risk
 By David Brinkerhoff
 NEW YORK, Jul 21 (Reuters) - 

A US federal court on Friday temporarily  barred drug maker Eli Lilly and Co. from making promotional claims that its osteoporosis drug raloxifene (Evista) has been shown to reduce the risk of breast cancer, rival drug maker AstraZeneca Plc said on Monday.

 AstraZeneca, the Anglo-Swedish pharmaceutical group, released a statement saying that a preliminary injunction barring  Indianapolis-based Lilly from making the claim was issued Friday by the US District Court of the Southern District of New York. "In the 106-page opinion, the court accepted AstraZeneca's position that Eli  Lilly's dissemination of false information has created a 'grave public health risk,'" AstraZeneca said.

Eli Lilly & Co. plans to take advantage of a federal ruling that allows drug company  representatives to show doctors medical articles describing alternative uses for medications. Wednesday's ruling by U.S.  District Court Judge Royce C. Lamberth, of Washington, D.C., could lead to more so-called ``off-label'' use of drugs and expand treatment options for patients. Eli Lilly said yesterday it will start instructing its 2,855-person U.S. sales force to take advantage of the widened marketing opportunities offered by the ruling.

 Lamberth's ruling applies only to peer-reviewed articles in medical journals and textbooks. Companies still aren't allowed to hand out their own brochures or make verbal sales pitches for off-label drug uses. 

For a long article which pulls together "Publications that contained information on the background of development, structure, mechanism of action, tissue-selective effects, and adverse effects of raloxifene" and supplies a long list of references, visit
http://www.acponline.org/journals/annals/02mar99/ralox.htm
Annals of Internal Medicine
CLINICAL REVIEW Clinical Effects of Raloxifene Hydrochloride in Women
Annals of Internal Medicine, 2 March 1999. 130:431-439

It is premature to recommend raloxifene use to lower the risk of developing breast cancer outside of a clinical trial setting. On the basis of available information, use of raloxifene should currently be reserved for its approved indication to prevent bone loss in postmenopausal women. 

    Raloxifene Approved for Osteoporosis

     Raloxifene (Evista, Lilly) 60-mg tablets have been approved by FDA for prevention of osteoporosis in postmenopausal women. The first selective estrogen receptor modulator, raloxifene should be available by early January. 

     FDA reviewed data from 50 studies conducted in 28 countries to establish the safety and efficacy of raloxifene for prevention of postmenopausal osteoporosis. More than 12,000 women have participated in the clinical program to date. A total of 1,764 postmenopausal women participated in pivotal Phase 3 osteoporosis prevention studies. In two studies, women were randomly assigned to take raloxifene or placebo. In the third study, women took raloxifene, placebo, or estrogen-replacement therapy. All the women took calcium supplements. In each study, raloxifene was superior when compared with placebo in preventing bone loss in the lumbar spine and hip. These pivotal clinical trials also showed that raloxifene builds bone, although to a lesser extent than does estrogen. 

     A rare but serious side effect associated with raloxifene was an increase in venous thromboembolic events. Women taking raloxifene reported a higher rate of hot flashes than did women taking placebo (24.6% versus 18.3%). Women taking raloxifene also reported a higher rate of leg cramps than did women taking placebo. Raloxifene did not increase the risk of endometrial or breast cancer. 

[ I found the discussion on whether bone density meant anything for the prevention of fractures most fascinating ]

I must thank Joan for suggesting the easy way to search for these hearings on the FDA website, limit the search to "Docket" it worked.

• http://www.fda.gov/
• click on search on left side column
• put search word such as raloxifene in box and highlight Docket  on right side.
• The second choice, the  *.rdf file can be downloaded to your hard drive for easier reading. This is a 292 page document.

The first presentation representing the public by Dr. Trudy Busch of the Women's Health Research Group at the University of Maryland is well worth reading. 

One of the other presenters suggested all women in the study should be followed after for 10 years, I wonder if that suggestion was taken up?: I don't really think it was.

What the Patient Should Know:

1. While taking raloxifene, it is important that patients avoid prolonged immobilization because of the increased risk of venous thrombosis. In the event that this situation is unavoidable, raloxifene should be discontinued 72 hours prior to the expected   time of immobilization. 
2. Raloxifene does not cure hot flashes. In addition, in some patients,  it may cause hot flashes as a side effect
3. Patients should be advised to take calcium and vitamin D  exercise should be considered. 
4. It is important that patients try to stop cigarette and/or alcohol consumption and to reduce other risk factors for osteoporosis. 
5. Raloxifene should only be used by postmenopausal women. 
6. While taking raloxifene, it is important to avoid becoming pregnant  because this drug can harm the fetus 
7. While on raloxifene therapy, do not take any form of estrogen therapy. 

 

I really don't want to confuse things here, but I just read a news report today that shows they want to use Raloxifene now also for pre menopausal women. They found that it *increases* estrogen levels in women who are still ovulating. 

But the news story does say: "It is important to know that the effects of raloxifene differ depending on a woman's present ovarian function," Baker said. "One should not generalise about the use of raloxifene between postmenopausal and premenopausal women." 
Yes this is  going to muddy the waters only a tad . 

The study on Raloxifene and premenopausal women is reported to be published in current issue of the Journal of Clinical Endocrinology and Metabolism

NB One of Lilly's justifications for ignoring cancer in tested rodents is that it will only be used in menopausal women

DR. LAUREN STREICHER: The confusion with Raloxifene, of course, is that everyone thinks this is it, this is an estrogen substitute. It is not meant to be an estrogen substitute, and it’s not being marketed as such. It is being marketed as an alternative to women who cannot take estrogen, who would like to prevent osteoporosis. It’s not going to help hot flashes, in fact, may increase hot flashes, and it may not--no one has really looked to see other tissues, in terms of is this going to benefit the bladder, is this going to help with Alzheimer’s, which we know that estrogen can. (Alzheimers is moot: Tishy)

DR. SAMUEL EPSTEIN, University of Illinois, Chicago: The alarming information is that in studies on mice and rats Raloxifene produces a high incidence of ovarian cancers. The end of the section dealing with these studies says the clinical relevance of this is not known. However, when you turn to the warning section on Raloxifene in which women are told about their dangers, there’s not a single mention about ovarian cancer. 

ELIZABETH BRACKETT: Do you think Raloxifene to be allowed on the market? 

DR. SAMUEL EPSTEIN: Under no circumstances. 

AS REPORTED in The Wall Street Journal, scientists will reveal at a cancer meeting next month that the designer estrogen raloxifene can cut breast cancer risk by up to 74 percent.
         But it's still too early to recommend the synthetic estrogen, according to Dr. Richard Klausner, director of the National Cancer Institute.
        The study was not designed to determine if raloxifene prevents breast cancer, but rather to find out if it wards off the bone-robbing disease osteoporosis, he noted. The finding that it also appeared to cut breast cancer risk was an unexpected, secondary effect. Thus, while fewer women taking the drug in the study developed breast cancer, the women were not necessarily at risk of the disease to begin with. The findings could have been due to chance alone.
        "We really do need long-term data on that [breast-cancer] finding before we can be absolutely sure that's a real effect," Dr. Robert Lindsay, president of the National Osteoporosis Foundation, told a conference recently.

A drug to prevent osteoporosis is also effective in lowering risk factors for cardiovascular disease in postmenopausal women, but is not as effective as hormone replacement therapy (HRT), according to an article in the May 13 issue of The Journal of American Medical Association (JAMA). 
The authors state that "this study demonstrates that raloxifene ... favorably alters several markers of cardiovascular risk in healthy postmenopausal women." However, they caution: "Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease." 

"The uncertainties about the cardioprotective effect of estrogens apply doubly to raloxifene. Even if estrogens were proven to be cardioprotective, a rush to replace estrogen with raloxifene for this indication still may be inappropriate. ... Raloxifene may be viewed as a designer drug, not yet suitable for everyday wear. Or, ultimately, it may prove to be a magic bullet in search of its target."