Hawthorn is the common name of a plant from which a popular herbal product is derived. The botanical drug is officially listed in the European Pharmacopoeia,1 and it is defined as consisting of the dried whole or cut flower-bearing branches of Crataegus monogyna Jacq (Lindm), or of C laevigata (Poir) DC or their hybrids, or more rarely other Crataegus species of the Rosaceae (rose family) is marketed in the United States as a dietary supplement. The fruit of this plant, although not official, also is used for the same health conditions.
Hawthorn has been used in folk medicine for the treatment of diarrhea, gall bladder disease, insomnia, and as an antispasmodic agent in the treatment of asthma.2 Historically, the Chinese used hawthorn for a variety of conditions; it was first promoted for "dropsy" in seventeenth century England.3 Hawthorn use for cardiac and circulatory disorders gained popularity in Europe in the nineteenth and beginning of the twentieth century when it was widely promoted by the Irish physician, Green.4-6 Thereafter, a commercial preparation of hawthorn was made available in the United States and suggested as a treatment for a wide variety of cardiovascular disorders. Clinically, hydroalcoholic extracts are sold as prescription medications widely in Europe and Asia. Hawthorn is approved for use in Germany for mild congestive heart failure (New York Heart Association [NYHA] class II).7-18 Hawthorn has been suggested as a therapy for left ventricular dysfunction, atherosclerosis, angina pectoris, and dysrhythmias related to ischemia. However, most available information in humans relates to its effect in patients with congestive heart failure. Therefore, this review will focus on hawthorn's use for this indication.
Members of the genus Crataegus are thorny shrubs or small trees having bright green, three to seven lobed leaves, and flowers grouped into branchy corymbs having five triangular sepals, five white petals, and an androecium of 15 to 20 stamens. Crataegus species are common to the temperate areas of the Northern Hemisphere, including east Asia, Europe, eastern North America, and parts of South America.19,20
Botanically, the genus is complex, and members have been classified under various names. For example, C laevigata (Poir) DC, the most commonly used source for hawthorn preparations, has been known synonymously as C oxyacantha L, C oxyacantha L ssp polygala Lev, C oxyacanthoides Thuill, and Mespilus oxyacantha (Gartn) Crantz.1,21,22C monogyna Jacq (Lindm), the second commonly used source plant material, has the synonyms of C apiifolia Medik non Michx, C oxyacantha L ssp monogyna Lev, Mespilus elegans Poir, M monogyna All, and M monogyna Ehrh.22 In addition to "hawthorn," members of this genus also have been known by other common names, including aubepine, weissdorn, épine blanche, espino blanco, harthorne, haw, hedge thorn, May thorn, whitethorn, and weissdorn.1,2,22,23
Chemically, the major chemical constituents are flavonoids and related proanthocyanidins, with the former being represented by rutin, hyperoside, vitexin, vitexin-2″ rhamnoside, acetylvitexin-2″ rhamnoside.24,25 In the influroescence, flavonol glycosides, mainly in the form of hyperoside, spiraeroside, and rutin, are present. The primary flavonoid derivatives found in the leaves are (−)-epicatechin and/or (+)-catechin, and the related procyanidins formed during condensation of two to eight monomeric units of the above compounds,24-27 together with oligomeric procyanidins.28 Simple phenolic acids (eg, chlorogenic and caffeic acids) also have been reported. Of the nonphenolic constituents, pentacyclic triterpenes such as ursolic and oleanolic acids and the 2-α-hydroxy derivative of the latter, known as crataegolic acid, are among the characteristic compounds. The chemical profile of the fruits (berries) is very similar to those of other flowering top parts. However, the amount of the individual flavonoids and oligomeric procyanidins is different, with the fruits containing more hyperoside and the leaves having higher contents of vitexin rhamnoside.21,29Fig 1 depicts structures of representative flavonoids and proanthocyanidins.
Hawthorn has a number of pharmacologic actions that could be considered advantageous in patients with left ventricular dysfunction. First, it has a mild positive inotropic effect that is possibly mediated by blockade of Na+-K+ ATPase (ie, similar to digitalis glycosides) and/or inhibition of phosphodiesterase III.30,31 It should be noted, however, that other positive inotropes, particularly those that inhibit phosphodiesterase (eg, amrinone and milrinone), have not fared well in long-term mortality trials.32 Hawthorn does have a vasodilating action both in the coronary circulation and the peripheral vasculature that may be mediated by inhibition of angiotensin-converting enzyme (ACE).33 One small animal study34 suggests that it also may possess adrenergic blocking activity. Of course, other drugs with beta blocking and ACE inhibitory activity have been conclusively shown to improve quality of life and decrease the mortality and morbidity associated with chronic heart failure35 and would place the potential of hawthorn in this disorder in a much more favorable light. It also has been suggested that hawthorn has a lipid-lowering effect (decrease in low-density lipoprotein [LDL] concentration and increased LDL receptor sensitivity), an antidysrhythmic action (through preventing ischemia or prolonging action potential duration), an ability to improve coronary blood flow (through vasodilation and possibly by promoting angiogenesis), and antioxidant activity.36-38
Numerous controlled and open clinical trials have assessed the therapeutic efficacy of Folium cum Flore Crataegi extracts for the treatment of stage II heart failure.8-12,14-17 All of the clinical studies originated in countries other than the United States, predominantly Germany.
The clinical investigations completed to date were performed with a dried extract of 70% aqueous/methanol or a 45% aqueous/ethanol standardized extract (2.2% flavonoids or 18.75% oligomeric procyanidins) from the leaves with flowers.13 The dosing ranged from 160 mg to 900 mg of the extract per day for 4 to 8 weeks. Evaluation of the therapeutic efficacy of the extracts was based on the following testing criteria: anaerobic threshold as measured by spiroergometry,10 clinical global impressions,14,15 exercise tolerance,8,14,15 ejection fraction,9,16 quality of life and improvement of subjective symptoms (NYHA),11,14,16,17 and pressure/rate product.11,14,15,17 Most clinical trials have evaluated relatively small groups of patients, with the primary outcomes being an improvement in exercise tolerance and subjective complaints of heart failure symptoms; examples are reviewed below. It is important to note that no published studies to date have examined mortality as an endpoint.
The efficacy of a standardized extract (2.2% flavonoids) on the improvement of exercise tolerance (measured by bicycle ergometry) was assessed in patients with cardiac insufficiency NYHA class II, in three separate clinical trials.8,14,15 Oral administration of the extract (300 mg/day) for 4 to 8 weeks improved working capacity, however, the difference was not statistically significant when compared with placebo.8 An 8-week, double-blind, placebo-controlled clinical trial assessed the efficacy of the extract (600 mg/day, oral) for the treatment of 78 patients with NYHA stage II heart failure.14 Patients in the treatment group had a significant improvement in exercise tolerance as measured by ergometer bicycle as compared with the placebo-treated group (p < .001). The treatment group also had a lower blood pressure and heart rate during exercise, and subjects had fewer overall symptoms such as dyspnea and fatigue.14 One-hundred and thirty-two patients with NYHA class II cardiac insufficiency were treated orally with 900 mg/day of the extract or 37.5 mg of Captopril for 8 weeks in a double-blind comparative trial.15 Exercise tolerance, as measured by ergometer bicycle on days 7, 28, and 56 of the study, improved in both groups (p < .001). In addition, the pressure-rate product was reduced, and the incidence and severity of symptoms such as dyspnea and fatigue decreased by approximately 50%.15
Another randomized, double-blind, placebo-controlled trial assessed the efficacy of a standardized extract (2.2% flavonoids) on exercise-induced anaerobic threshold, as measured by spiroergometry in 72 patients.10 Patients were administered an oral dose of 900 mg/day of the extract or matching placebo for 8 weeks. The outcomes measured were defined as oxygen uptake, tolerance period until anaerobic threshold was reached, and when exercise was discontinued. After 8 weeks of treatment, oxygen uptake increased in the treated group (p < .05), and exercise time to anaerobic threshold increased by 30 seconds in the treated group, but only 2 seconds in the placebo group. Significant improvements in subjective symptoms also were noted in the treated group, as compared with placebo (p < .01).10
A number of studies appear to demonstrate that hawthorn has a clinically detectable positive inotropic action as shown by its ability to increase ejection fraction. In an uncontrolled trial involving seven patients with stage II to III heart failure, oral administration of 240 mg/day (18.75% oligomeric procyanidins) of an extract of the leaves with flowers increased the ejection fraction from 30% to 41%, as measured by angiography.16 Symptomatic complaints also showed improvements.16 The effects of a standardized extract (18.75% oligomeric procyanidins) on hemodynamics were investigated by gated angiography in an open study.9 Twenty patients diagnosed with NYHA stage II heart failure, with a left ventricular ejection fraction of < 55%, were treated with 480 mg of a standardized extract of the leaves with flowers (18.75% oligomeric procyanidins).9 After 4 weeks of treatment, the ejection fraction at rest increased from 40% to 45% and from 42% to 47% under exercise conditions. Ergometric tolerance to exercise improved, blood pressure decreased, and subjective complaints also were reduced.9
In summary, the existing clinical literature shows promise for hawthorn as an adjunctive agent for the treatment of left ventricular dysfunction. Small controlled trials are consistent in demonstrating hawthorn's ability to improve exercise tolerance and symptoms of mild to moderate heart failure. Further, there is preliminary evidence that hawthorn may improve left ventricular performance as measured by ejection fraction. It should be noted that the rather large increase in ejection fraction observed in some trials is more than likely a function of small sample size. It is unlikely that these large increases would remain consistent in larger clinical trials. Regardless, the paradox of heart failure is that a number of drugs that improve symptoms and indices of ventricular function in fact have led to worsened survival (eg, intermittent dobutamine, phosphodiesterase inhibitors, flosequinan), whereas others without overt or only subtle hemodynamic benefit (beta blockers, ACE inhibitors) improve survival and now form the cornerstone of modern therapy in these patients.
The existing literature regarding hawthorn is plagued by small sample sizes with variable and surrogate endpoints (eg, ejection fraction, exercise duration). Therefore, what is clearly needed in order to put hawthorn in its proper place in the treatment of heart failure is a large, controlled, multicenter trial in which mortality serves as the primary endpoint. Such a trial is now ongoing and referred to as the SPICE (Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in CHF) trial.38 The SPICE trial began in October 1998 and will enroll approximately 2,300 patients from seven European countries. Patients with NYHA class II or III heart failure (ischemic or non-ischemic in etiology) will be randomized to placebo or 900 mg of a dry extract of hawthorn leaves and flowers standardized to 84.3 mg of oligomeric procyanidins in tablet form. All patients will receive standard therapy for heart failure (eg, digoxin, diuretics, ACE inhibitors, and beta blockers). The primary outcome is "time to first event," defined as a composite of death from cardiac cause, non-fatal myocardial infarction, and hospitalization due to heart failure. Secondary endpoints include quality of life and pharmacoeconomic analyses. Echocardiography will be performed at baseline and at 6, 12, and 24 months of follow-up. Completion is expected during 2002.
Few pharmacokinetic studies (beyond initial animal studies with radio-labeled drug) exist, so the characteristics of metabolism and elimination of hawthorn and its ingredients remain largely unknown. Absorption of a 14C-labeled procyanidins fraction was measured in mice after intragastric administration. The results showed that 20% to 30% of the total fraction, 40% to 81% of the trimeric procyanidins, and 16% to 42% of the oligomeric procyanidins were absorbed within 1 to 7 hours.39 After 7 hours, 0.6% of the radioactivity of the total fraction was eliminated by expiration and 6.4% was eliminated in the urine. Daily intragastric administration of 0.6 mg of the radio-labeled total oligomeric procyanidin fraction to mice for 7 days led to an accumulation of radioactivity that was two to three times higher than that of a single dose.39 Because the primary route of elimination of hawthorn is not fully known, it would be prudent to use lower doses in patients with major organ (hepatic, renal) dysfunction. Whether hawthorn is a substrate or inhibitor of specific cytochrome P450 or phase II enzymes is not known; pharmacokinetic drug interactions have not been described.40 Some pharmacodynamic interactions have been listed in reviews and herbal textbooks (eg, with other agents with inotropic or vasodilatory actions) but no primary literature could be found to document these instances in patients. The most widely cited drug interaction is with digoxin,41 which purportedly leads to additive pharmacologic and toxic effects because both agents block the sodium-potassium pump. However, again no studies to support this could be located. Indeed, ongoing large multicenter trials (eg, SPICE) allow and do not discourage the concurrent use of hawthorn and digoxin.
Hawthorn is well tolerated by most patients. In the clinical trials reviewed, reports of adverse effects are virtually nonexistent. Rash has been rarely reported.37 A mild sedative effect and gastrointestinal complaints are listed in some review sources, but documentation is lacking in the published clinical trials. Animal experiments showed that a standardized hydroalcoholic extract (18.75% oligomeric procyanidins) is well tolerated in rodents without any clinical symptoms of toxicity and that it was not mutagenic.42 Although a Crataegus fluid extract (1:1) was moderately active in the Ames mutagenicity test in Salmonella typhimurium TA98, the activity was observed only after metabolic activation and appeared to be due to the quercetin content of the extract; however, the amount of quercetin ingested in a normal daily diet is higher than the amount present in the plant extract.43
WARNINGS AND PRECAUTIONS
Hawthorn, if used, should be restricted to patients with mild heart failure and viewed as adjunctive treatment to standard therapies. It should not be used in patients in lieu of drugs proven to prolong life and improve symptoms of heart failure. The patient should report any worsening of heart failure symptoms or episodes of chest discomfort. Therapeutic effects may require 4 to 6 weeks of continued therapy.44
DOSAGE FORMS AND POSOLOGY
Hawthorn is available as dried crude drug for infusion and hydroalcoholic extracts formulated into various dosage forms:
- Herbal tea: 1.0 to 1.5 g comminuted drug as an infusion three to four times daily45
- Hydroalcoholic extract (45% ethanol or 70% methanol; drug/extract ratio 4-7:1) standardized to contain 18.75% oligomeric procyanidins (calculated as epicatechin) or 2.2% flavonoids (calculated as hyperoside), 160 to 900 mg/day.9-12,14-17,44
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