Clinical trial paperBlack cohosh with or without St. John's wort for symptom-specific climacteric treatment—Results of a large-scale, controlled, observational study
Introduction
The menopausal transition is very frequently accompanied by hot flushes, sleep disturbances or mood changes [1], [2], [3], [4]. A recent estimate puts the percentages of women experiencing such symptoms during menopause at 85% [5]. In addition, a large proportion of women resort to self-medications with over-the-counter (OTC) medications or complementary and alternative medications (CAM) [6].
After the Women's Health Initiative Study (WHI) shed doubt on the value of hormone replacement therapy (HRT) [7] the interest in alternative therapies has increased. Among herbal remedies to alleviate menopausal complaints, the most common are preparations based on Black cohosh (Actaea racemosa, formerly called Cimicifuga racemosa). The effects of Black cohosh are commonly attributed to the two main constituent groups, i.e. triterpene glycosides (actein, 27-deoxyactein, cimicifugoside) and cinnamic acid esters [8], [9]. The research on Black cohosh is recognized also by the American Herbal Pharmacopoeia [10], World Health Organization and others. Most of the data available on the efficacy and safety have been obtained with the commercially available preparation Remifemin® (Remifemin; Schaper & Brümmer GmbH & Co. KG, Salzgitter, Germany) based on 2.5 mg native isopropanolic Black cohosh extract (isopropanolic C. racemosa = iCR), corresponding to approximately 20 mg herbal rootstock matter per tablet.
Each tablet of the combination preparation Remifemin® plus contains 3.75 mg iCR extract and 70 mg of an ethanolic extract from 245 to 350 mg St. John's wort (Hypericum perforatum), a dosage recommended by the German Commission E. The efficacy of St. John's wort for the treatment of mild depression has been demonstrated in numerous clinical studies [11]. Guidelines from the American College of Physicians–American Society of Internal Medicine state that St. John's wort may be considered for short-term treatment of mild acute depression [12].
Both Black cohosh-based preparations have been shown to be effective and well-tolerated in placebo-controlled randomized clinical trials using standardized efficacy assessment methods [13], [14]. Osmers et al. showed daily administration of the Remifemin monotherapy preparation to improve Menopause Rating Scale (MRS) [15] score by 0.03 to 0.05 units compared with placebo over a period of 12 weeks in 304 subjects; a similar effect to those with hormone replacement therapy. In a study by Uebelhack et al. of the combination preparation with H. perforatum in 301 subjects with pronounced psychological symptoms, both MRS score and the summary score on the Hamilton Depression Rating Scale improved with active treatment compared with placebo over 16 weeks of treatment. In both these randomized trials, there were no relevant group differences in adverse events, laboratory findings, or tolerability.
However, randomized controlled clinical trials represent an artificial situation that does not necessarily correspond to that encountered by individuals taking medications in daily life. The efficacy and safety of drugs depend on a variety of factors and patients’ treatment patterns are seldom as standardized as in closely monitored randomized trials, which are based on highly selected study populations, specified outcomes and restricted use of other therapies. The enormous number of women affected by menopausal symptoms results in huge variation within the patient population that would be difficult to capture in randomized studies. Thus, there is a need for data on the usage patterns (the prescribing behavior under conditions of everyday medical practice) and on the effectiveness of both products in such settings. The primary objective of this study was to prove superiority of Remifemin® plus versus Remifemin® on psychological symptoms after 3 months of treatment. The choice of primary variable was governed by the main difference between the two preparations used in the study, i.e., the presence of St. John's Wort in Remifemin® plus. For this purpose, a large-scale, non-randomized, observational design was chosen.
Section snippets
Study design
This was a prospective, non-randomized, open-label observational study conducted between March 2002 and March 2004 in 1287 outpatient gynecologists’ practices from all parts of Germany. The study design and conduct was in accordance with the German federal recommendations for the conduct of observational trials [16]. Included were women with any menopausal symptoms. Exclusion criteria were treatment with any study medication during the previous 6 months and hormone replacement therapy (HRT) in
Patient disposition and demographics
A total of 6141 women were enrolled in 1287 practices. They received at least one dose of study medication and effectiveness data was reported at least once, thus qualifying for inclusion in the ITT population. Of the enrolled subjects, 3027 (49%) received the monotherapy, mostly as tablets (n = 2798; 46%) but in a few cases (n = 229; 4%) as solution. The combination preparation was administered to 3114 subjects (51%). During the course of the study, 244 subjects (4%) changed treatment from
Discussion
The risks associated with hormone replacement therapy (HRT) demonstrated by the Women's Health Initiative Study in 2002 [7] highlighted the need for a differentiated approach to the management of menopausal symptoms [21]. The data presented here, from a large-scale observational study, provide information on prescription patterns, long-term effectiveness and tolerability of two herbal preparations based on Black cohosh (C. racemosa) across a wide range of menopausal patient types in everyday
Acknowledgment
Financial support for this study was provided by Schaper and Brümmer GmbH & Co. KG, Salzgitter, Germany.
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