Hawthorn (Crataegus monogyna, C. laevigata, Rosaceae) is one of the most popular herbal products in the United States, ranking 24^th in total single herb sales for 2007 in mainstream food, drug, and general retail stores (see Market Report on page 60 for details). It is marketed in some European countries as a prescription medicine. Hawthorn extract is used to treat chronic heart failure, and extracts of hawthorn leaf and flower are approved by Germany's Commission E for the treatment of New York Heart Association (NYHA) stage II heart failure.¹ This systematic review of 14 double-blind, placebo-controlled, randomized clinical trials on hawthorn extract in the treatment of chronic heart failure by the Cochrane Collaboration includes a meta-analysis of the data from 10 clinical trials.

Through database searches, hand searches of bibliographies and personal libraries, and expert contacts, the authors identified clinical trials on the treatment of NYHA-categorized chronic heart failure in adults taking hawthorn leaf with flower extract mono-preparations. The databases searched included the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and Digital Dissertations. The trials were read and assessed by 2 independent reviewers, with a third reviewer resolving any disagreements. The quality of the trial methods, including randomization methods and control for selection bias, were assessed and assigned letter grades.

Fourteen trials with a total of 1,110 patients were included in the review. The majority used parallel study designs, and 2 trials used cross-over designs. The trials included a range of 30 to 209 subjects. The hawthorn preparations used in the clinical trials were dosed at 160-1,800 mg/day of either (1) Crataegus Special Extract WS 1442 (Dr. Willmar Schwabe GmbH; Karlsruhe, Germany*), which is standardized to 18.8% oligomeric procyanidins, or (2) the standardized LI 132 hawthorn extract (Faros® 300, Lichtwer Pharma GmbH, Germany**).

In the majority of the trials, hawthorn extract was used as an adjunct to conventional medications for chronic heart failure, including diuretics (4 trials) and ACE inhibitors (3 trials). The trial durations were 3-16 weeks, and 26 weeks was the longest follow-up period. There was a great deal of variation in methodological quality among the trials. The authors write that 6 of the 14 trials "reported adequate sequence generation" and that 3 trials reported "adequate allocation concealment." The maximal workload, assessed using bicycle ergometry with an increase of 25 Watts every 2 minutes until the patient needs to stop, was the most common outcome.

The meta-analysis of trials reporting maximal workload showed a significant increase in patients receiving hawthorn extract, when compared with those receiving a placebo (n=380, 95I 0.71 to 10.00, P<0.02). Five trials assessed the pressure-heart rate product (the systolic blood pressure in mm Hg multiplied by the heart rate per minute and divided by 100). The meta-analysis showed a significant reduction in the pressure-heart rate product (n=264,

19.22 mmHg/min, 95I -30.46 to -7.98). Two trials assessed exercise tolerance, and they showed a significant increase (n=98, +122.76 Watt X min, 95I 32.74 to 212.78). The studies also showed an improvement in symptoms including fatigue and shortness of breath. Two trials used the van Zerssen symptom score, and they showed a significant effect favoring hawthorn extract (n=239, WMD -5.47, 95I -8.68 to -2.26). One trial showed a significant reduction in left ventricular ejection fraction (n=40, WMD.70%, 95I 0.88 to 2.52). Another trial found no significant effect on 6-minute-walk test between the placebo and hawthorn extract group. Only one trial reported mortality rates, with 3 deaths in the hawthorn group and one in the placebo group. The most commonly reported adverse events were dizziness, vertigo, and gastrointestinal complaints. (Note: Because this was not a safety review, there can be no cause-effect relationship inferred between hawthorn extract and the reported adverse effects. Hawthorn has a well-documented history of safe use, and common adverse events are possible in almost any study population.) Five trials reported no adverse events in subjects receiving hawthorn extract.

The authors recommend that rigorous, long-term clinical trials assessing clinical outcomes including cardiac death, as well as physiological outcomes, are needed. They warn against self-treatment by heart failure patients and recommend against hawthorn extract as a good candidate for over-the-counter or dietary supplement sales (insofar as patients are not able to self-diagnose or adequately self-treat such conditions). However, reported adverse events are mild and transient, and one study showed no interaction between hawthorn extract and digoxin, a common heart failure drug. Data from animal studies do indicate the potential of interactions between hawthorn extract and cardiac glycoside, anticoagulant, and antihypertensive drugs, although clinical research is needed for confirmation. The authors conclude that "The best evidence that is available suggests that hawthorn extract has significant benefits, compared with placebo, as an adjunctive treatment for patients with chronic heart failure."