HORSE CHESTNUT SEED EXTRACT (AESCULUS HIPPOCASTANUM)

VI. HORSE CHESTNUT SEED EXTRACT (AESCULUS HIPPOCASTANUM)

Horse chestnut seed extracts are often used for chronic venous insufficiency (CVI). A systematic review(12) included eight placebo-controlled trials and five trials conducted against reference treatments. They included a total of 1083 patients with CVI of moderate severity. The methodological quality of these trials was on average good (Jadad score = 3–5). The overall results indicated that active treatment is significantly more effective than placebo and equivalent to reference treatments. Both objective signs and subjective symptoms responded to treatment. On the basis of these findings we con- cluded that ‘‘horse chestnut seed extract is superior to placebo and as effective as reference medications in alleviating the objective signs and subjective symptoms of CVI’’ (12).

To date no systematic reviewhas addressed the safety of horse chestnut seed extract. Adverse effects include pruritus, nausea, gastrointestinal upset, bleeding, nephropathy, and allergic reactions. Horse chestnut seed extract may increase the effects of anticoagulants and should therefore be discon- tinued before major surgery (7).

On balance, the benefits of horse chestnut seed extracts seem to outweigh its risks, which are rare and usually minor. The standard treatment for CVI is, of course, external compression (i.e., compression stockings). Compliance with this treatment is, however, notoriously poor. Thus horse chestnut seed extracts could play an important role in the treatment of this condition.

VII. KAVA (PIPER METHYSTICUM FORST) Kava is used mostly for the symptomatic treatment of anxiety. A systematic

review(13) included seven placebo-controlled, double-blind RCTs with a total of 477 patients. The methodological quality of these studies was on average good (Jadad score = 2–5). All trials yielded positive results (weighted mean difference was 9.69, 95% CI = 3.54–15.83). Comparative trials suggest therapeutic equivalence with synthetic anxiolytics. Our overall conclusion was that ‘‘kava extract is superior to placebo as a symptomatic treatment for anxiety’’ (13).

A systematic reviewof the safety of kava has been published (14). It revealed a range of mild and transient adverse effects. However, the suspicion has recently arisen that kava might cause liver damage. As of August 2002, 68

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such cases had been reported worldwide. Some of these cases were serious, but causality is difficult to establish on the basis of such (mostly incomplete) reports. Based on this evidence, kava has been taken off the market in several European countries (15). Until further data become available, the use of kava should not be recommended.

VIII. SAW PALMETTO (SERENOA REPENS) Sawpalmetto is used for benign prostate hyperplasia (BPH). A meta-analysis

(16) of 18 RCTs included 2939 patients with this condition. The methodo- logical quality of these studies was variable but some were of the highest standard. The results of the meta-analysis revealed a weighted mean differ- ence in symptom score of

1.41 points (95% CI = 2.52–0.30). This corresponds to a statistically significant and clinically relevant improvement of BPH symptoms compared to placebo. One important caveat is the lack of long-term data, particularly as the treatment of BPH is by definition long- term. The authors of this meta-analysis concluded that ‘‘Serenoa repens improves urologic symptoms and flowmeasures’’ (16).

No systematic reviewof the safety of sawpalmetto is available at present. Adverse effects include breast tenderness, gastrointestinal com- plaints, constipation, diarrhea, dysuria, and decreased libido (7). Sawpal- metto has hormonal effects and could therefore interact with hormone therapies.

One can conclude from this collective evidence that the risk-benefit profile of sawpalmetto is encouraging. Its adverse effects are rare and usually mild; its therapeutic potential to relieve the symptoms of BPH is considerable. It can therefore be recommended for BPH patients who prefer a herbal to a synthetic drug treatment.

IX. ST. JOHN’S WORT (HYPERICUM PERFORATUM) St. John’s wort is used mostly for mild to moderate depression. There are

numerous systematic reviews of St. John’s wort. The first meta-analysis (17) included 23 RCTs with a total of 1757 patients. The methodological quality of trials was variable but some were excellent. The results of the meta-analysis clearly showed that St. John’s wort is more effective than placebo or as effective as synthetic antidepressants. This finding has been confirmed by several subsequent systematic reviews. The evidence comparing St. John’s wort with conventional antidepressants is, however, still relatively weak. Recently, several RCTs have produced negative results. It is important to note that these related to severe rather than mild to moderate depression. The authors of the original meta-analysis (17) concluded that ‘‘extracts of Hyper-

Systematic Reviews of HMPs 853

icum are more effective than placebo in the treatment of mild to moderate depression.’’ This conclusion still holds and is corroborated by newtrial data that have become available since then (18).

A systematic reviewof the safety of St. John’s wort (19) pooled all relevant data from case reports, clinical trials, postmarketing surveillance, and drug-monitoring studies. Collectively this evidence suggested that St. John’s wort is well tolerated with an incidence of adverse effects similar to that of placebo. The most common adverse effects were gastrointestinal symp- toms, dizziness/confusion, and tiredness/sedation. A potentially serious adverse effect is photosensitivity, but this appears to occur extremely rarely. Since the publication of this revieww e have learned much about the interactions between St. John’s wort and other drugs (20). Extracts of St. John’s wort activate enzymes of the cytochrome P450 system, namely CYP3A4. It can therefore lower the plasma levels of a range of drugs given concomitantly; cyclosporin, oral contraceptives, phenoprocoumon, warfarin, amitriptyline, indinavir, and digoxin. When used with other SSRIs it can cause a serotonin syndrome.

On balance, the benefits of St. John’s wort as a symptomatic treatment of mild to moderate depression outweigh its risks—provided, of course, that these risks are managed adequately. Essentially St. John’s wort should not be combined with drugs metabolized via the cytochrome P450 enzyme system.

X. DISCUSSION Systematic reviews (including meta-analyses) represent the most conclusive

evidence for or against efficacy and safety. This holds for all medical interventions, and HMPs are no exception. However, this approach is not totally free of limitations. For instance, if one submits flawed RCTs to a systematic review, the result will necessarily be flawed as well. Publication bias is another important problem. We knowthat negative trials tend to remain unpublished (21). Thus the published evidence might, in some cases, be biased toward a false-positive overall result.

The English medical literature is demonstrably biased toward positive results, and negative trials thus tend to emerge in journals published in other languages (22). It is therefore important to not restrict systematic reviews to the English literature. In herbal medicine this is perhaps more important than in other areas since much of the primary trial data used to be published in German.

Further problems with systematic reviews of HMPs relate to the (lack of) standardization of extracts. If one preparation of a given herb is shown to be effective, this does not necessarily apply to another preparation of the same herb. Systematic reviews are therefore at risk of generating a mislead-

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ing overall result. There is no easy way around this problem except insisting that all HMPs, particularly those used in clinical trials, are adequately standardized.

The evidence summarized in this chapter clearly shows that not all HMPs have been demonstrated to do more good than harm. It is simply not possible to generalize across different HMPs, and every set of data has to be evaluated on its own merit. On the other hand, the evidence also clearly demonstrates that not all HMPs are clinically useless. In fact, most of the HMPs discussed above are powerful drugs. It is therefore obvious that they should be adequately regulated. In many countries (e.g., United States and England), HMPs are marketed as dietary supplements, a status that invites suboptimal quality as well as multiple other problems and therefore does not provide a regulatory framework for the adequate protection of the consumer.

In conclusion, some HMPs have been investigated in sufficient depth to allowtentative risk-benefit assessments. In doing this, each HMP has to be judged on its own merit—generalizations about the risks or benefits of HMPs are counterproductive.

REFERENCES 1. Eisenberg D, David RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler

RC. Trends in alternative medicine use in the United States; 1990–1997. JAMA 1998; 280: 1569–1575. 2. Gruenwald J. The supplement markets in the US and Europe. Nutraceuti World 2000 July/August; 36–37. 3. Ernst E, White AR. The BBC survey of complementary medicine use in the UK. Complement Ther Med 2000; 8:32–36. 4. Ha¨usermann D, Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Wachsendes Vertrauen in Naturheilmittel. Extracts of feverfewmay inhibit platelet behavior via neutralization of sulphydryl groups. Dtsch A¨rzteblatt 1997; 94:1857–1858. 5. Ernst E, De Smet PAGM, ShawD, Murray V. Traditional remedies and the ‘‘test of time.’’ Eur J Clin Pharmacol 1998; 54:99–100. 6. Ernst E. Herbal medicinal products: an overviewof systematic reviews and meta- analyses. Perfusion 2001; 14:398–404. 7. Ernst E, Pittler MH, Stevinson C, White AR, Eisenberg D. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby, 2001. 8. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for the prevention and treatment of the common cold. The Cochrane Library, 1999. Oxford. Update software. 9. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. Ann Intern Med 2000; 133:420–429. 10. Ernst E, Pittler MH. Ginkgo biloba for dementia: a systematic reviewof double- blind placebo-controlled trials. Clin Drug Invest 1999; 17:301–308.

Systematic Reviews of HMPs 855 11. Pittler MH, Schmidt K, Ernst E. Hawthorn extract for treating chronic heart

failure: a meta-analysis of randomised trials. Am J Med 2003; 114:665–674.

12. Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency: a criteria-based systematic review. Arch Dermatol 1998; 134:1356–1360.

13. Pittler MH, Ernst E. Efficacy of kava extract for treating anxiety: systematic reviewand meta-analysis. J Clin Psychopharmacol 2000; 20:84–89. 14. Stevinson C, Huntley A, Ernst E. A systematic reviewof the safety of kava extract in the treatment of anxiety. Drug Safety 2002; 25:251–261. 15. Ernst E. Safety concerns about kava. Lancet 2002; 359:1865. 16. Wilt TJ, Ishani A, Stark G, MacDonald R, Lau J, MulrowC. Sawpalmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998; 280:1576. 17. Linde K, Ramirez G, MulrowCD, Paul A, Weidenhammer W, Melchart D. St. John’s wort for depression—an overview and meta-analysis of randomised clinical trials. Br Med J 1996; 313:253–258. 18. Stevinson C, Ernst E. Hypericum for depression: an update of the clinical evidence. Eur Neuropsychopharmacol 1999; 9:501–505. 19. Ernst E, Rand JI, Barnes J, Stevinson C. Adverse effects profile of the herbal antidepressant St. John’s wort (Hypericum perforatum L.). Eur J Clin Pharmacol 1998; 54:589–594. 20. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 2001; 15:2163–2175. 21. Easterbrook PJ, Berlin JA, Gopalan R, Mathews DR. Publication bias in clinical research. Lancet 1991; 337:867–872. 22. Egger M, Zellweger-Za¨hner T, Schneider M, Junker C, Lengeler C, Antes G. Language bias in randomised controlled trials published in English and German. Lancet 1997; 350:326–329.