Katherine M. Newton, PhD; Susan D. Reed, MD, MPH; Andrea Z. LaCroix, PhD; Louis C. Grothaus, MS; Kelly Ehrlich, MS; Jane Guiltinan, ND
Acknowledgments: The authors acknowledge all those who contributed significantly to this work, especially the 351 dedicated women who participated in this study. In particular, they thank Linda Palmer, RN, and Jill Seymour, RN, ARNP, for their outstanding work with study participants; David Carrell and Nirmala Sandhu for their excellent programming and data management; Sheree Miller, PharmD, Lead Pharmacist, Investigational Drug Services, University of Washington Medical Center, for packaging and assuring blinding of study medications; and the late Natalie Koether, JD, Pure World, Inc., South Hackensack, New Jersey, for providing black cohosh. The authors also thank the members of the Data and Safety Monitoring Committee: Drs. Gregory Burke (Chair), Ellen Gold, Susan Johnson, and Barry Storer.
Grant Support: This project was funded by the National Institute on Aging and the National Center for Complementary and Alternative Medicine (grant R01AG17057) and by an administrative supplement from the National Institute on Aging (Alternative Therapies For Menopause—A Randomized Trial: Herbal Alternatives Quality Control Supplement).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Katherine M. Newton, PhD, Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101; e-mail, email@example.com.
Current Author Addresses: Dr. Newton: Center for Health Studies, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Reed: Obstetrics and Gynecology, Harborview Medical Center, P.O. Box 359865, Seattle, WA 98104.
Dr. LaCroix: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109.
Mr. Grothaus and Ms. Ehrlich: Group Health Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.
Dr. Guiltinan: Bastyr University, 3670 Stone Way North, Seattle, WA 98103.
Author Contributions: Conception and design: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, K. Ehrlich, J. Guiltinan.
Analysis and interpretation of the data: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, J. Guiltinan.
Drafting of the article: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, J. Guiltinan.
Critical revision of the article for important intellectual content: K.M. Newton, S.D. Reed, A.Z. LaCroix, L.C. Grothaus, K. Ehrlich, J. Guiltinan.
Final approval of the article: K.M. Newton, S.D. Reed, A.Z. LaCroix, K. Ehrlich.
Provision of study materials or patients: S.D. Reed.
Statistical expertise: A.Z. LaCroix, L.C. Grothaus.
Obtaining of funding: K.M. Newton, S.D. Reed, A.Z. LaCroix.
Administrative, technical, or logistic support: K. Ehrlich.
Collection and assembly of data: K.M. Newton, L.C. Grothaus, K. Ehrlich.
Herbal supplements are widely used for vasomotor symptoms.
To test the efficacy of 3 herbal regimens and hormone therapy for relief of vasomotor symptoms compared with placebo.
1-year randomized, double-blind, placebo-controlled trial conducted from May 2001 to September 2004.
Group Health, Washington State.
351 women age 45 to 55 years with 2 or more vasomotor symptoms per day; 52% of the women were in menopausal transition and 48% were postmenopausal.
Rate and intensity of vasomotor symptoms (1 = mild to 3 = severe), and Wiklund Vasomotor Symptom Subscale.
1) Black cohosh, 160 mg daily; 2) multibotanical with black cohosh, 200 mg daily, and 9 other ingredients; 3) multibotanical plus dietary soy counseling; 4) conjugated equine estrogen, 0.625 mg daily, with or without medroxyprogesterone acetate, 2.5 mg daily; or 5) placebo.
Vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale score did not differ between the herbal interventions and placebo at 3, 6, or 12 months or for the average over all the follow-up time points (P > 0.05 for all comparisons) with 1 exception: At 12 months, symptom intensity was significantly worse with the multibotanical plus soy intervention than with placebo (P = 0.016). The difference in vasomotor symptoms per day between placebo and any of the herbal treatments at any time point was less than 1 symptom per day; for the average over all the follow-up time points, the difference was less than 0.55 symptom per day. The difference for hormone therapy versus placebo was −4.06 vasomotor symptoms per day for the average over all the follow-up time points (95% CI, −5.93 to −2.19 symptoms per day; P < 0.001).
The trial did not simulate the whole-person approach used by naturopathic physicians. Differences between treatment groups smaller than 1.5 Vasomotor symptoms per day cannot be ruled out.
Black cohosh used in isolation, or as part of a multibotanical regimen, shows little potential as an important therapy for relief of vasomotor symptoms.
Clinical Trials Registration number: NCT00169299.
Caution about taking estrogen for treating postmenopausal vasomotor symptoms has led to increasing substitution of herbal regimens despite few tests of their effectiveness.
The authors randomly assigned 351 perimenopausal or postmenopausal women to herbal treatments (black cohosh, multibotanicals, or multibotanicals plus counseling about dietary soy), estrogen with or without progesterone, or placebo. At 3, 6, and 12 months, patients receiving the herbal interventions had the same change in vasomotor symptoms as those receiving placebo (except for more severe symptoms at 12 months for patients taking multibotanicals plus dietary soy). Estrogen substantially decreased vasomotor symptoms.
Most participants were white and were well-educated.
Herbal regimens did not reduce postmenopausal vasomotor symptoms in this sample of women.
Participant recruitment and retention, Herbal Alternatives for Menopause Trial (HALT).
Reasons for discontinuing therapy are not mutually exclusive. All participants received allocated intervention. *In the original enrolled plan, all participants were enrolled in 1 of 5 groups. †After publication of the Women's Health Initiative (WHI) estrogen–progestin (E + P) trial (2), women were given the option of 4-arm (without conjugated equine estrogen [CEE]) or 5-arm randomization. ‡After publication of the WHI Memory Study (8, 9), randomization to CEE was stopped and only 4-arm randomization (that is, random assignment to herb or placebo, excluding hormone therapy) was used. BMD = bone mineral density; FSH = follicle-stimulating hormone; HT = estrogen with or without progestin; MPA = medroxyprogesterone acetate, 2.5 mg (women without a uterus were randomly assigned to CEE only); soy = counseling to increase dietary soy; TSH = thyroid-stimulating hormone.
Table 1. Baseline Clinical and Demographic Characteristics by Randomization Group
Adjusted mean number of vasomotor symptoms per day, by study group.
Adjusted for age (continuous), body mass index (kg/m2, continuous), hysterectomy (yes or no), previous use of hormone therapy (HT) (yes or no), menopausal status (menopausal transition vs. postmenopausal), and randomization arm (4-arm without hormone therapy vs. 5-arm with hormone therapy).
Adjusted mean Wiklund Vasomotor Symptom Subscale scores, by study group.
Table 2. Difference in Adjusted Mean Change in Vasomotor Symptom Frequency and Intensity and Wiklund Vasomotor Symptom Subscale Score between Intervention and Placebo Groups*
Table 3. Difference in Adjusted Mean Change in Frequency of Hot Flashes and Night Sweats and Wiklund Menopause Symptom Scale Scores between Intervention and Placebo Groups*
Table 4. Women with Adverse Events, Mean Adherence, and Reasons for Withdrawal or Discontinuation of Medication Use by Treatment Group over 12 Months of Follow-up
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In a study, black cohosh was found ineffective as a treatment for symptoms of menopause.
Jonathan P. Krueger
December 19, 2006
why between-subjects design?
Is there some reason a within-subjects design was not used? It would appear to be suited to the phenomenon, which is reversible and observable within months. Why not have all subjects experience all conditions, say two months per condition, ordered at random for each subject?The power would be better, the results cleaner, and we'd be able to answer a question this study cannot: do some subjects repond reliably, even if the overall response is weak?
China Clinical Trials Coordination Center
December 20, 2006
Interpretation of the "negative" result
I read the paper with interest about the excellent work completed by Dr. Newton and her colleagues. We have just finished a pilot study of a black cohosh ethanol abstract in Beijing and are on the track of a national wide multi-centered RCT. The double-blinded pilot study enrolled 120 Chinese women with climacteric symptoms who were stratified into perimenopausal and postmenopausal arms, according to the standard of STRAW. Each arm was divided into 3 interventional groups, i.e. black cohosh (BC) low dose (1# bid), BC high dose (1# tid) and placebo, with 20 cases in each group. The primary outcome was Kupperman Index (KI) evaluated before the study and at the 2 and 4 weeks after the treatment. We also used menopause rating scale (MRS) as secondary outcome when it was first introduced in China and validified by this study. Although some of the results of this pilot study were "negative" (even there existed difference between BC and placebo groups), similar as shown in Dr. Newton et al's study, we were very careful to accept the null hypothesis, which we believed that the sample size we calculated before the study was not powerful enough to detect the difference.
I've noticed in Dr. Newton et al's study that they calculated the sample size based on an assumption that the effect of herbs was halfway of HRT. It is not surprised to see that the black cohosh group failed to show a "P<0.05" when it didn't reach the standard effect size even though the 95% CIs shifted to the left side of zero and inferred a small sample size. Seems Dr. Altman's words ring again beside our ears absence of evidence is not an evidence of absence. I have also noticed that Dr. Newton and her colleagues also admitted that their study result didn't rule out the differences between treatment groups smaller than 1.5 vasomotor symptoms per day.
We have never used Wiklund Vasomotor Symptom Subscale in China. But we found an interesting result in our study when we used both KI and MRS as outcomes, of which the KI seemed more "sensitive" to detect the treatment effect than MRS. We postulated that it was possible due the "weight" factor given to the score of vasomotor symptoms in KI which might "amplify" the effect comparing scored by MRS. It is interesting to know if any other researchers find similar phenomena.
Our study showed that the BC treatment brought more adverse events than placebo to the participants, mainly headaches. It was also shown in many other studies on BC. I was surprised to find that BC treatment had similar safety profile as placebo in Dr. Newton et al's study. We used a pharmaceutical product with major components specified, provided by a local manufacturer. Dr. Newton didn't mention whether the components contained in the BC product were standardized.
We appreciate that Dr. Newton or any other medical professionals with experience of using BC may share information with us.
Dr. Baoming Ge
Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995;311:485
Dr. Ge is the medical director of a CRO, located in Beijing, China.
Private medical practitioner
December 29, 2006
A misguided trial of Cohosh
Neither black nor blue Cohosh is indicated in any herbal/homeopathic text book for menopausal vasomotor symptoms sothat this trial is of no value in this respect. Unfortunately not one of your auhors is mentioned as being a fully qualified physician as well as a fully qualified and certified homeopath, in which case it would have been a far more useful to have compared homeopathically prepared Sepia,Sulphur,Lachesis or Pulsatilla.
The time is really long overdue for orthodox medicine to take a genuine look at the enormous potential for other therapies
The misunderstanding of herbal/homeopathic potential
Jonathan R. Byron
Dosage Low, Conclusions Sweeping
The dosages used in this study (160 mg daily of black cohosh root or 200 mg daily of black cohosh and other botanicals) are much lower than that taken by many women. Some commonly used supplements contain 500 mg or more of C. racemosa root per capsule, and multiple capsules are taken per day. It is not unusual to see a daily dose that is ten times larger than that used in this experiment. Assuming there is a dose-dependency to previously demonstrated phytoestrogen properties of black cohosh, it is unfortunate that this study only looked at relatively low doses. This study made a sweeping conclusion (that black cohosh "shows little potential as an important therapy for relief of vasomotor symptoms") that may or may not be true, but which is not supported by the study design. Research to evaluate ethnobotanical practices should start with a better understanding of those practices.
mid western univ
December 27, 2006
Was an excellent article, clearly illustrating the benefits of Black Cohosh, Multibotanicals, Soy, Hormone Therapy in menpause. My congrats to the authors.
Robert E. Kaeufeler
Max Zeller Soehne AG
January 19, 2007
Are conclusions of the HALT-study on herbal remedy really sound?
It is important that the authors' claim regarding the efficacy of black cohosh be considered in the context of an unusually high placebo response and an unclearly defined black cohosh dose. Even allowing for natural symptom regression over time, the placebo response in this study warrants further scrutiny. There was a consistent reduction in symptoms in the placebo group in the first 6 months (reduction from baseline in all other groups became stable after 3 months) and over a 1-year period only one patient in this group discontinued due to lack of symptom relief. This drop out rate was even proportionally less than among patients in the HRT group. Unusually high placebo responses in clinical trials can mask true drug responses and may be due to flaws in study design or implementation. Changes introduced following the publication of the WHI study led to 16 patients being unblinded and may also have been responsible for marked baseline differences observed among treatment groups, in particular between the HRT group and the others. The validity and clinical relevance of the findings of this study may also be undermined by the dosage and type of black cohosh extract used. Although the authors state that the effects of herbal products may be sensitive to dose and extraction method, they have not addressed these issues in the study. The amount of triterpene glycosides which is discussed constitutes not at all to the active substance of black cohosh and authors have not specified the extract used in the study according to current and international regulatory guidelines and standards . This study therefore does not negate the results of previous studies that have demonstrated the efficacy of black cohosh. The WHI study had previously shown an increased risk of cardiovascular disease and breast cancer in women using HRT . In light of new evidence which suggest that the recent fall in the incidence of breast cancer rates in the United States may be due to a reduction in hormone use , black cohosh should continue to be considered an alternative treatment of menopausal symptoms.
1. CPMP/QWP/2819/00 Rev 1
2. Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama, 2002. 288(3): p. 321-33.
3. Ravdin, P.M., et al. A sharp decrease in breast cancer incidence in the United States in 2003. in San Antonio Breast Cancer Symposium. 2006.
The author is Medical Director of Max Zeller Soehne AG, Switzerland. The company produces its own black cohosh extract Ze 450.
Katherine M. Newton
March 22, 2007
We would like to reply to two points made in this review. First, is the issues of the select nature of the populations we studies, and resulting generalizability. We do not disagree with this point which applies to virtually any study. However, it is important to note that we made conscious choices to increase the generalizability compared to many of the currently published studies. We included women who were in the menopause transition as well as post-menopausal women, we included women with as few as 2 hot flashes per days vs. the 7 or more per day that is often required, and we included women with and without a uterus. The fact that our results were consistent across these different characteristics is, we believe, a point in favour of generalizability. It should also be clarified that we did not mail 150,000 letters to women with qualifying symptoms. Rather, the mailings went to presumably age-eligible women, but we could not target those with hot flashes specifically. And women received 2-3 mailings over time, so the number of women approached was closer to 60,000. The large number of mailings was necessary because the number of women with qualifying hot flashes who were willing to accept randomization in a clinical trial, and not already taking an alternative therapy or HT, is relatively small. The population base is far superior to studies enrolling women who present for symptoms, who represent just the tip of the iceberg.
It is suggested that a better evaluation of compliance with the soy intervention would have been urine or plasma phytoestrogens. We agree, and we will be publishing these results in the future.
Katherine M. Newton, PhD Associate Director for Research Group Health Center for Health Studies 1730 Minor Ave., Ste 1600 Seattle, WA 98101 Phone: 206-287-2973 FAX: 206-287-2871 Email: firstname.lastname@example.org
Susan D. Reed, MD, MPH Associate Professor of Obstetrics and Gynecology School of Medicine University of Washington Seattle, WA
Andrea Z. LaCroix, PhD Professor of Epidemiology Public Health Sciences Division, Fred Hutchinson Cancer Research Center Seattle, WA
I am the first author of this manuscript.
Katherine M Newton
Group Health Center for Health Studies
June 20, 2007
Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormonal Thera
We do not agree with Mr. Krueger that a within-subject design would have been preferable. A valid crossover study requires sufficient time for the effects of one drug to "wash out" before treatment on a second drug is begin. The time needed for the effects of herbal treatments to wash out is unknown so a crossover study would be subject to the criticism that the effects of one drug contaminated the effects of the others. Exposing each woman to all treatments would have required 14 months of participation, introducing unnecessary logistical and analytic complexity. This approach would have negated our opportunity to evaluate bone mineral density and to examine adverse events associated with longer duration of therapy. Menopausal symptoms change through time, further complicating the interpretation of crossover studies. Dr. Ge raises one of the principle limitations of many studies of alternative therapies for menopause symptoms, the use of generalized scales to summarize the menopause experience. These scales use a single question or small sets of questions for each outcome (hot flashes, mood, etc). As Dr. Ge observed, changes in scale scores are usually driven by vasomotor symptoms. We believe it is preferable to use validated, outcome- specific instruments (hot flash diaries and sternal skin conductance for vasomotor symptoms, PHQ-9 for depression, etc). Our study was powered to rule out differences between treatment groups greater than 1.5 vasomotor symptoms per day, a change we consider quite small.
One cannot conclude that there was a large placebo effect in the HALT study simply because symptoms decrease from baseline to month 3 in the placebo group. Subjects were excluded if they did not have at least 2 symptoms per day. We expected symptoms to decline from baseline to month 3 due to regression to the mean. Also, change in the placebo group was minimal from months 3 to 12 so it is incorrect to claim that there was a placebo effect after month 3.
Black cohosh was standardized to 2.5% triterpine glycosides. The doses we used were those most frequently used by naturopathic physicians in Seattle at the time, were consistent with manufacturer recommendations, and are considerably higher than doses currently recommended by many manufacturers (40-80mg). We are unaware of recommendations for doses as high as 1000-1500mg and consider such a practice inadvisable. Dr. Byron may be confusing the dose of dried root with that for standardized extract.
Katherine M. Newton, Susan D. Reed, Andrea Z. LaCroix, Louis C. Grothaus, Kelly Ehrlich, Jane Guiltinan. Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo: A Randomized Trial. Ann Intern Med. 2006;145:869–879. doi: 10.7326/0003-4819-145-12-200612190-00003
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Published: Ann Intern Med. 2006;145(12):869-879.
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