Three Systematic Reviews of Echinacea Clinical Trials Suggest Efficacy with Cold Symptoms

Reviewed: Linde K, Barrett B, Wolkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold (review). The Cochrane Library. 2006;1:1-39.

Reviewed: Schoop R, Klein P, Suter A, Johnston S. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther. 2006;28( 2):174-183.

Reviewed: Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of echinacea for the prevention and treatment of the common cold: A meta-analysis of randomized, controlled trials [abstract and poster]. Amer Coll Clin Pharmacol. September 2006.

In 2006, 3 meta-analyses reviewed clinical trials on various species of Echinacea (Asteraceae) and determined that the preponderance of published evidence still supports some benefits for the now somewhat beleaguered herb. A meta-analysis for the Cochrane Collaboration by Linde et al and another by Schoop et al were published evaluating the relative efficacy of echinacea preparations. A yet-to-be published third meta-analysis concluded that the controlled clinical trials reviewed supported a positive assessment for echinacea preparations (Shah et al, 2006).

Over a year has elapsed since the highly publicized clinical trial by Turner et al( n1) in the New England Journal of Medicine in which 3 preparations made from the extract of the root of Echinacea angustifolia were deemed ineffective in preventing or treating upper respiratory tract infections in healthy college students inoculated with a rhinovirus. The widespread reporting of these negative results, when added to negative outcomes of other well-controlled echinacea trials,( n2, n3, n4) has created considerable confusion among health professionals, the media, and the general public about the relative value of echinacea preparations.

In the case of both the reviews by Linde et al and Schoop et al, some interesting benefits can be attributed to various types of echinacea preparations, as noted by Bruce Barrett, MD, PhD, in a recent editorial in HerbalGram.( n5) After reviewing all the relevant clinical trials published on echinacea preparations as well as the Schoop review, Dr. Barrett, one of North America's most knowledgeable experts on echinacea clinical trials and a co-author of the Linde et al meta-analysis, concluded that "Echinacea remains a reasonable choice for prevention or treatment of the common cold, as sadly, there are few if any well-proven remedies, conventional or alternative."( n5)[*]

The assessment of echinacea's effectiveness is complicated for several reasons: ( 1) 3 different species (Echinacea angustifolia, E. purpurea, and E. pallida) are used medicinally; ( 2) different parts of the plant (root, herb, flower, or whole plant) are used in various preparations; ( 3) various preparation methods are used in production (dried herb material, extraction, fresh-pressed juice, etc.); ( 4) some echinacea preparations contain combinations of species, plant parts and/or types of preparation methods; and ( 5) some echinacea-based products also contain other plant extracts or (in other countries) homeopathic components.[†]
The Linde et al Review

The objective of Linde et al's updated systematic review was to evaluate whether evidence exists from randomized controlled trials (RCTs) that echinacea preparations are more effective than no treatment, more effective than placebo, or about as effective as other treatments in preventing and treating the common cold. An interesting aspect of this review is the inclusion of pharmaceutical experts as authors to better examine outcome data from primary studies.

In the Linde et al review, the authors conducted a literature search to identify RCTs of the effectiveness of echinacea preparations in preventing and treating nonspecific viral and other types of upper respiratory tract infections. To be included in the review, the studies had to contain clinical outcome measures related to the occurrence (prevention studies), duration, or severity (treatment studies) of infection. Studies of combinations of echinacea with other herbs were excluded. The following databases were searched: the Cochrane Central Register of Controlled Trials (2005), PubMed (1997 to April 2005), EMBASE (1998 to June 2005), AMED (through August 2005), and the Centre for Complementary Medicine Research (1988 to May 2005). At least 2 authors independently assessed the quality of the identified trials for eligibility in this review. For the prevention trials, the outcomes of interest were the number of subjects with one or more colds, the duration of the colds, and the severity of the colds. For the treatment trials, the outcome measures were total symptom scores, nasal symptoms, and the duration of the colds.

For this review, 16 studies met the inclusion criteria: 5 from the United States, 5 from Germany, 3 from Canada, 2 from Sweden, and 1 from Russia. Most of these studies were rated as being of "reasonable to good methodological quality." Two of the studies were classified as prevention trials, 5 as self-treatment trials, and 9 as treatment trials. There were a total of 20 experimental groups in the 16 trials reviewed.

In the 2 prevention trials, no significant differences between the echinaceat-reated and placebo groups were found with regard to the number of participants with colds or the duration or severity of the colds. One treatment trial with a no-treatment comparison group showed a trend towards better symptom scores in children with colds who received a freshly expressed juice preparation of E. purpurea aerial parts. One trial that tested the efficacy of pressed juice from the aerial part of E. purpurea in preventing "the full picture of a cold" in persons with early cold symptoms showed a significant effect over placebo. Of 6 trials that measured the effects of 5 different echinacea preparations on the severity and duration of colds relative to the effect of placebo, only 2 showed a significant effect over placebo.

Only one of the trials reviewed compared the effectiveness of an echinacea preparation with that of a non-echinacea intervention (a proprietary herbal preparation containing extracts of the leaves of andrographis [Andrographis paniculata, Acanthaceae] and the roots of eleuthero [Eleutberococcus senticosus, Araliaceae]-known as SHA-10 or Kang Jang®, Swedish Herbal Institute, Goteborg, Sweden). The results of that trial showed that the non-echinacea intervention decreased the severity of cold symptoms in children significantly better than did a fresh-pressed juice preparation of E. purpurea aerial tops. Of the 16 trials reviewed, the primary authors and the reviewers concluded that 9 trials showed significant effects over placebo, 1 showed a trend in favor of the echinacea preparation, and 6 showed no significant differences between the echinacea-treated groups and the comparison groups.

These trials covered a total of 2601 subjects (3447 if all randomized subjects are considered); these include 411 subjects as participants in prevention trials, 1064 in self-treatment trials (1910 were randomized but only 1064 actually were infected with a cold and started treatment), and 1126 in treatment trials (K. Linde, e-mail to M. Blumenthal, December, 12, 2006).

The main findings of this systematic review were as follows:

1. The variety of commercially available echinacea-containing products assessed contained different amounts of bioactive compounds and cannot be considered biochemically comparable.
2. The methods used to assess cold variables in the trial subjects were highly variable.
3. Most of the trials reviewed had reasonable to good methodology based on assessment of 2 independent reviewers using the Jadad method.( n6)
4. Preparations based on the aerial parts of E. purpurea "[may] be effective in the early treatment of colds in adults, but results are not fully consistent." There is no clear evidence that other preparations work or that children benefit.
5. Adverse side effects associated with echinacea preparations were infrequent or minor and mostly similar to placebo. Rashes were reported in one trial in children.( n7)

The authors note that the findings were not easy to interpret because of the heterogeneity of the products tested, because other unpublished and probably negative trials exist that were not identified, and because the results of the placebo controlled treatment and self-treatment trials were "clearly positive…or negative." The authors expected that a larger number of trials would show "less extreme results."

Linde et al also state that it is important that consumers be aware of the great differences between echinacea-containing products and that most of these products have not undergone clinical testing. The German Commission E, an expert panel of the German government that has evaluated the safety and efficacy of about 300 herbs and herb combinations, has recommended that those echinacea preparations that were approved for use at the time (i.e., from aerial parts of E. purpurea and roots of E. pallida) not be used for longer than 8 weeks because after this period, if the symptoms for which the echinacea is being used (i.e., upper respiratory tract infections or lower urinary tract infections--the 2 indications for which echinacea preparations were approved) were not resolved, then more aggressive therapy (e.g., conventional pharmaceutical drugs) was probably required.( n8) Due to the widespread use of echinacea products, these authors write that "further research is clearly desirable." This review contains several pages of tabular data containing detailed characteristics of the 16 studies reviewed, including the specific echinacea preparations studied, dosages, treatment periods, and subject data. Some characteristics of other trials of echinacea that were not included in this review are also listed.
The Schoop et al Review

Echoing the results of the review by Linde et al, the authors of the second systematic review (in this case, a meta-analysis) reported that the efficacy of echinacea preparations, as a whole body, remains uncertain because there are clinical trials published with both positive and negative findings. Whereas evidence for efficacy in the treatment of cold episodes exists, conclusive proof for the preventative efficacy of echinacea preparations has been lacking so far. These authors (Schoop et al) write that the efficacy of echinacea extracts as assessed in clinical trials basically seems to depend on the quality of the product (raw material, standardization, preparation, etc.) or the dosage utilized. The purpose of this meta-analysis was to determine whether the negative findings from prevention trials were a consequence of lack of efficacy (as has been widely reported by some media) or of inadequate sample size of the number of subjects in each trial.

In this meta-analysis researchers in Switzerland, Germany, and the UK conducted a systematic search of electronic databases. Search terms included echinacea, black Sampson, coneflower, and Roter Sonnenhut (English and German common names for various species of echinacea). The inclusion criteria for this review required that studies had to deal with direct inoculation with a pathogen rather than spontaneously developed common colds; i.e., the trials had to be based on a design in which the patients were intentionally exposed to a rhinovirus (usually sprayed into the nose) as opposed to looking at a particular population and measuring the incidence of infection with colds via chance. The clinical trials identified were assessed for suitability using Quality of Reporting of Meta-analyses criteria. The primary outcome of the trials in this meta-analysis was the development of symptomatic clinical cold.

Three inoculation studies were identified that were of high quality, randomized, double-blind, and placebo-controlled. None of these 3 trials were included in the meta-analysis by Linde et al described above. All 3 used similar inoculation protocols and standardized echinacea products for investigation, thereby allowing the data from all 3 trials to be pooled, i.e., combined into one dataset for analysis. To summarize the 3 studies, prophylactic treatment started 7 or 14 days before virus challenge and continued until day 5 or day 7. The studies used 300 mg of E. purpurea extract 3 times daily [Note: the original study does not describe the product used in this trial], 300 mg or E. angustifolia root extract 3 times daily, E. purpurea above-ground plant parts 3 times daily (176 mg EchinaGuard® [Echinacin®] Madaus GmbH, Cologne, Germany), or a placebo. Additional information on the products was not described in the meta-analysis.

There were a total of 390 subjects in the 3 combined studies. Based on the meta-analysis, the likelihood of experiencing a common cold was 55% higher with placebo than with echinacea. Overall echinacea preparations (as opposed to placebo) were effective in reducing the incidence of (i.e., preventing) symptoms of the common cold after clinical inoculation.

According to the authors, this was the first meta-analysis to find prophylactic efficacy of standardized echinacea preparations. A clinical study would need to include 340 patients per group to detect the effect found in this meta-analysis with a statistical power of 80% and a significance level of 5%. The findings support the results of randomized, double-blind, placebo-controlled clinical trials that report the efficacy of echinacea preparations for the prevention of spontaneous colds. A limitation of this meta-analysis was the low number of eligible studies. Large clinical trials are needed to confirm the finding. According to the lead author of the present meta-analysis (R. Schoop, a scientist at Bioforce AG in Switzerland, the manufacturer of one of the echinacea products that was clinically tested and included in the meta-analysis), the results of this meta-analysis challenge the conclusions drawn from the high profile rhinovirus challenge trial in the New England Journal of Medicine( n1) and renews the discussion about the efficacy of echinacea preparations in preventing symptoms of the common cold (R. Schoop e-mail to M. Blumenthal, March 2, 2006).
The Shah et al Review

The third review on echinacea in the past year has not yet been published. It was presented as a poster abstract at the American College of Clinical Pharmacology in September 2006 (Shah et al, 2006) but is reported as currently in press (S. Shah e-mail to M. Blumenthal, February 12, 2007). The authors, from the University of Connecticut School of Pharmacy, searched the following databases for all RCTs on echinacea preparations from 1966 to April 2006: Medline, CINAHL, Web of Science, and the Cochrane Database of Systematic Reviews, as well as conducting a search of references used for the Echinacea monograph in the Natural Medicines Comprehensive Database. Incidence of the common cold was reported as an odds ratio (OR) with 95% confidence interval, while duration of the common cold was reported as the weighted mean difference (WMD) with 95% confidence interval.

In all, 14 studies reporting incidence or duration data were included, encompassing 1,356 and 1,630 participants, respectively. This review demonstrated that the echinacea preparations used in the respective trials in total decreased the odds of developing the common cold by 58% [OR 0.42 (95%CI 0.25 to 0.71)] and the duration of a cold by 1.9 days [WMD -1.85 (95%CI -2.76 to -0.96)]. The authors conclude, "The totality of current evidence supports Echinacea's benefit in decreasing the incidence and duration of the common cold." Although it is reportedly in press, since the results of this meta-analysis have yet to be published in a peer reviewed journal, it is possible that the statistical data may change upon additional rigorous analysis.

The conclusions of these systematic reviews, when viewed as a body of literature, based on the preponderance of the evidence from published RCTs on various types of echinacea preparations, supports the proposition that there is benefit in the rational use of various echinacea preparations for either prevention or treatment of symptoms of upper respiratory tract infections related to colds or flu.

[*] Dr. Barrett's comments were written before he reviewed the clinical trials on COLD-fX® (CVT-E002; CV Technologies, Edmonton, Alberta, Canada), a polysaccharide-based special extract from the roots of North American ginseng (Panax quinquefolius L., Araliaceae), for a literature review on this patented preparation to be published by the American Botanical Council in 200Z Nor do his comments include the research that has been conducted on the andrographis-eleuthero extract fixed combination (SHA-10, Kang Jang®, Swedish Herbal Institute), as noted in this article, for which there are numerous published clinical trials strongly suggesting safety and efficacy in treating upper respiratory tract infections secondary to colds and flu.

[†] "Regulations in the United States do not allow for the mixing of herbs or other dietary supplement ingredients (technically foods under US law) with homeopathic materials (technically regulated as drugs).

PHOTO (COLOR): Echinacea Stained glass by Dennis V.C. Awang. Mark Blumenthal collection. Photo @2007 ABC
References

(n1.) Turner RB, Bauer g, Woelkart K, Hulsey TC, Gangemi JD. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med. 2005;353(4):341-348.

(n2.) Sperber SJ, Shah LP, Gilbert RD, Ritchey TW, Monto AS. Echinacea purpurea for prevention of experimental rhinovirus colds. Clin Infect Dis. May 2004;38(10): 1367-1371.

(n3.) Yale SH, Liu K. Echinaceapurpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med. June 2004;164(11):1237-1241.

(n4.) Blumenthal M. Echinacea purpurea herb preparations ineffective in two trials for preventing and treating colds. HerbalGram. 2005;66:28-29.

(n5.) Barrett B. New review on echinacea reinvigorates debate on evidence of popular herb's benefits [editorial]. HerbalGram 2006;70:36-37,39.

(n6.) Jadad AR, Moore RA, Carrol D, et al. Assessing the quality of reports of randomized trials: is blinding necessary? Controlled Clin Trials. 1996;17:1-12.

(n7.) Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA. 2003;290:2824-30.

(n8.) Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister RS, eds. Klein S, Rister RS, trans. The Complete German Commission E Monographs Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; Boston: Integrative Medicine Communication; 1998.

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By Mark Blumenthal; Brenda Milot and Heather S. Oliff

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