Hawthorn Leaves and Flowers in CHF

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An overview of the various clinical trials using standardized hydro-alcoholic hawthorn extracts to treat patients with chronic heart failure reveals several changes

Table 8.1 Herbal preparations of hawthorn used in the studies summarised in the meta-analysis and the systematic review

Medication

Drug-extract ratio Extract

Daily dosage

Compound thought to be responsible for efficacy

Cardiplant 450 4-6.6:1

Ethanol

1-2 tablets (450 to

18.75% procyanidins

45%

900 mg dry extract)

(78-90.6 mg OPC)

-dry-

-standardised-

Faros 300

4-7:1

Methanol

3 x 1 coated tablets

2,2 % flavonoids

70%

(900 mg dry extract)

-standardised-

-dry-

Crataegisan

1:3.2

Ethanol

3 x 30 drops (approx.

6.4 mg procyanidins

49%

2.25 ml)

-liquid-

12.7 mg total of phenols

12.7 mg total of phenols in the past two decades: a gradual rise in the stage of heart failure (from I to III according NYHA) and the intervention itself, that is to say in the daily dosage (from 160 to 1800 mg) as well as the treatment period (from 3 to 24 weeks and a randomized controlled trial - RCT over 2 years - not yet published).

Some of these clinical trials have been analysed in a meta-analysis which facilitates a close look at the evidence from randomized controlled trials (RCTs) [39,40]. In that publication, from the quite high number of 26 potentially relevant studies, 13 could be included because they met the inclusion criteria (e.g. RCT, chronic heart failure, monopreparations). From the remaining 13 trials the data of 5 were not sufficient for pooling for meta-analytic evaluation. However, 8 trials could be analysed regarding efficacy but had to be divided into two groups according to their primary endpoint. In 4 trials [41-44] this was a change in maximal workload measured in watts (W) using bicycle ergometry. Here the pooled data of 310 patients with CHF NYHA I-III showed a significant increase of 7W ([95 % CI 3-11]; p < 0.01) under verum (dosage: 180 to 1800 mg daily, duration: 3 to 16 weeks) compared to placebo. In four further trials [45-48] the primary outcome was a different target: the pressure-heart rate product which was also measured in one [41] of the previous four trials, bringing the total number of trials to five. Here the pooled data of 264 patients with CHF NYHA I-II showed a significant reduction of minus 20 mm Hg/min ([95 % CI -32 to -8]; p-value not given) under verum (dosage: 160 to 240 mg daily, duration: 6 to 12 weeks). The third primary outcome evaluated in the meta-analysis was the exercise tolerance in 98 patients in two of the trials already mentioned above [41,43], but the result was not significant.

One must take into account that the study results are mostly based on a concomitant treatment of patients with hawthorn preparations in addition to other medications to treat CHF (e.g. diuretics, calcium antagonists, ACE inhibitors). Reflecting this, the results show the additional value of hawthorn along with standard treatment.

In what follows, we discuss trials which were not evaluated in the meta-analysis. Yet some of the older studies will not be discussed here due to an unclear definition of patient groups [49-53] or herbal preparation [54].

Iwamoto et al. 1981 conducted a controlled double-blind study in 102 patients with heart disease of ischaemic and/or hypertensive origin (mostly NYHA Stages II and partly III) to evaluate the efficacy of Crataegutt vs. placebo (3 x 2 dragees of an extract from leaves, flowers and fruits or placebo over 6 weeks). The analysis of 80 patients (14 excluded for non-adherence to the test plan, 8 dropped out) showed a general improvement and improvement in cardiac function under verum vs. placebo (p < 0.01) as well as improvement in subjective symptoms (p < 0.001; for individual subjective symptoms verum vs. placebo: dyspnoea, palpitation p < 0.01, cardiac oedemas p < 0.05). No group differences were noted for ECG. Side effects were observed in one patient under verum [55].

Eichstadt showed in patients with NYHA II, after 4 weeks of treatment with an extract from leaves and flowers (3 x 2 dragee), a significant (one-sided test) increase of the left ventricular ejection fraction from 40.2% to 43.5% at rest and 41.5% to 46.6% under exercise (radionuclide-ventriculography), a slight reduction in blood pressure at rest and reduction in the systolic pressure under exercise (188 mm Hg to 177 mm Hg); the frequency remained unchanged [56].

Schmidt et al. analysed 78 patients with NYHA II in a RCT (daily dosage: 600 mg hawthorn extract, duration: 8 weeks) [57]. After the 1-week wash-out phase cardial medication (e.g. heart glycosides, 6-blocker, ACE inhibitor) was not allowed except for diuretics if the dosage was stable for the 4 weeks prior to the study. The analysis showed a significant increase in the primary parameter, maximal workload on bicycle ergometry, of 12.5 W (p < 0.001) vs. placebo at the end of the trial. The improvements in the secondary parameters like RR, heart rate, and subjective symptom reduction were significant, too.

Tauchert et al. performed the only available direct comparison between hawthorn and an ACE inhibitor. In a RCT with 132 patients suffering from CHF NYHA II, they showed that the treatment over 8 weeks with a daily dosage of either 900 mg hawthorn extract (leaves and flowers) or 37.5 mg Captopril led to a significant improvement in the maximum workload in each group (hawthorn: 14; Captopril: 16 W). Yet, the group difference was not significant, suggesting a comparable efficacy of both interventions [58].

Until recently no long-term data have been available for the treatment of patients with CHF with hawthorn extracts. Yet in 1998 the SPICE (Survival and Prognosis Investigation of Crataegus Extract) trial started. Aside from the study protocol [59], only some preliminary results, presented at the meeting of the American College of Cardiology, are available. After 2 years the treatment of 2681 patients with NYHA II to III with daily 900 mg hawthorn extract concomitantly with standard medication showed no benefit over placebo in the primary outcome (composite of cardiovascular mortality such as sudden cardiac death, heart failure death, fatal myocardial infarction) [37]. Yet there seems to be evidence for efficacy in a subgroup of pa tients. However, the concomitant use of hawthorn with standard therapy was regarded as safe.

Hawthorn preparations are mentioned in connection with elevated blood pressure (RR). To date, the clinical evidence on that topic remains inconclusive: Tauchert et al. examined RR as one of the secondary parameters in the above-mentioned comparison trial [58]. This target did not show a significant reduction in the hawthorn group but under Captopril.

Schmidt et al. found a significant reduction in RR, which was a secondary parameter in their above-mentioned RCT [57].

The pilot study of Walker et al. (n = 36; daily dosage: either 500 mg hawthorn extract or 600 mg Mg or a combination of both or placebo; duration: 10 weeks) showed a reduction in RR which was insignificant [60]. Nevertheless the authors regarded the results as promising and suggested to perform a randomised trial.

Yet, in that RCT Walker et al. [61] examined a different hawthorn extract than the one they have analysed in the pilot study. 79 hypertensive patients with type 2 diabetes (70% under hypotensive treatment) were treated (daily dosis: 1200 mg extract; duration: 16 weeks). The study showed a small but significant decrease in diastolic blood pressure in the hawthorn group vs. placebo (-2.6mmHg; p = 0.035).

8.2.6 Hawthorn Berries in CHF

Although clinical research has focused on hawthorn preparations from leaves and flowers, some trials on berries are available and have been summarized within a systematic review [14]. This review showed that three clinical trials examined pharmacological aspects referring to orthostatic dysregulation and two were on chronic heart failure NYHA II, but only one of them with a monopreparation. This RCT evaluated the efficacy and safety of a hydroethanolic extract of hawthorn berries (n = 143; 30 drops 3 times daily for 8 weeks). The efficacy analysis in the ITT population showed a significant improvement in the exercise tolerance of 8.3 W in the verum group vs. placebo ([95% CI -16.3 to -0.3]; p = 0.045), which was confirmed in the PP population [62]. It is noteworthy that in this trial standard medication to treat chronic heart failure was not allowed. The safety analysis revealed that only mild to moderate adverse events occurred and were statistically insignificant between verum (n = 9) and placebo (n = 11). They ranged from gastrointestinal to musculoskeletal, respiratory and psychiatric events and were unlikely to be related to the medication.

Even in the herbal preparations from hawthorn which have been examined in RCTs (not to mention the variety of other preparations freely available on the market), the question of phyto-equivalence seems to be an unsolved one.

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