363-369 - degenring 02074b

Phytomedicine 10: 363–369, 2003 Urban & Fischer Verlag Phytomedicine
http: //www.urbanfischer.de/journals/phytomed A randomised double blind placebo controlled clinical trial
of a standardised extract of fresh Crataegus berries
(Crataegisan®) in the treatment of patients
with congestive heart failure NYHA II
F. H. Degenring1, A. Suter1, M. Weber1, and R. Saller2 1 Bioforce AG, Roggwil, Switzerland2 Department of Internal Medicine, Universitätsspital Zürich, Switzerland A placebo controlled, randomised, parallel group, multicentre trial conducted in accordance with the
guidelines of Good Clinical Practice (GCP) shows the efficacy and safety of a standardised extract of
fresh berries of Crataegus oxyacantha L. and monogyna Jacq. (Crataegisan®) in patients with cardiac
failure NYHA class II.
A total of 143 patients (72 men, 71 women, mean age of 64.8 (8.0 years) were recruited and treated with
3 times 30 drops of the extract (n = 69) or placebo (n = 74) for 8 weeks. The primary variable for the
evaluation of efficacy was the change in exercise tolerance determined with bicycle exercise testing,
secondary variables included the blood pressure-heart rate product (BHP). Subjective cardiac symp-
toms at rest and at higher levels of exertion were assessed by the patient on a categorical rating scale.
An overall assessment of efficacy at the final visit was provided by the patient and the investigator.
In the ITT population there was a significant increase in exercise tolerance in both groups between visit
1 and visit 3. The difference between the treatment groups was 8.3 watts in favour of the standardised
extract of fresh Crataegus berries (p = 0.045). The result is confirmed in the PP population (p = 0.047).
Changes in BHP at 50 watts and at comparable maximum load were in favour of Crataegus extract but
the results are not statistically significant. The subjective assessment of cardiac symptoms at rest and
at higher levels of exertion did not change significantly and the patient and investigator overall assess-
ment of efficacy were similar for the two groups.
The medication was well tolerated and had a high level of patient acceptability.
The significant improvement, due to the fact that dyspnoea and fatigue do not occur until a significant-
ly higher wattage has been reached in the bicycle exercise testing allows the conclusion that the recruit-
ed NYHA II patients may expect an improvement in their heart failure condition under long term ther-
apy with the standardised extract of fresh Crataegus berries.
Key words: crataegus extract, crataegus berries, hawthorn, congestive heart failure, exercise tolerance,
randomised double-blind placebo controlled trial
᭿ Introduction
Heart failure is the inability of the heart to supply the chaemic heart disease and hypertension. Left ventricu- body with the required blood volume and occurs in lar systolic dysfunction is the most common finding in about 1% of the population, with an increasing morbid- patients with heart failure. Symptoms include dysp- ity rate in the elderly. The most common causes are is- noea and fatigue and the New York Heart Association (NYHA) has recognised four stages of the disease until subjective or objective discontinuation criteria oc- (class I, II, III, IV). An early start of a long-term thera- curred (Table 1). An electrocardiogram (ECG) was per- py is recommended already for the milder forms of formed and blood pressure and pulse determined at rest heart failure (NYHA classes I and II) to stop further de- and at the end of each watt setting. The maximum de- terioration in cardiac output and to improve the medi- pression of the ST segment (lead I or V ) after a load of um-term prognosis of these patients. However, classes 50 watts was documented, as were any symptoms ex- I and II often remain untreated due to side effects of perienced by the patient during the test. standard therapies. The reported excellent safety of Patients attended for follow-up at one and two Crataegus extracts suggests its use for early treatment months (visits 2 and 3) after the first visit. Changes in and in prevention of decreasing cardiac performance.
concomitant medication, adverse events and subjective Hawthorn (Crataegus oxyacantha) has a long histo- cardiac symptoms were recorded. The exercise toler- ry as a medical substance. The active ingredients are ance test was repeated. At visit 3 the overall efficacy of thought to be oligomeric procyanidines and flavonoids.
the treatment was assessed by the investigator and pa- Preclinical trials of hawthorn preparations have tient, and tolerability and acceptability of treatment demonstrated a positive inotropic effect on human heart muscle in addition to a reduction in stimulus Randomisation to active or placebo medication was threshold and a coronary vasodilative action (Ammon at visit 1 by means of a computer-generated randomisa- et al. 1981). Only in few studies objective and clinical tion list in which the medication was distributed in relevant parameters like exercise tolerance were tested.
blocks of four. Patients were allocated to the lowest Primary outcome in older studies were subjective available study number. The Clinical Trial Supplies of the CRO dispersed the study medication to the investi- Several placebo controlled clinical studies have gators. They received for each patient a sealed carton- demonstrated the efficacy of extracts of flowers and box containing two bottles of the study medication leaves of hawthorn in the treatment of cardiac insuffi- which they dispensed at visits 1 and 2. The returned ciency of NYHA Class II and with higher doses even medication at visits 2 and 3 was weighed. Compliance III (WHO Monograph, 1998; Zapfe, 2001). In a recent was checked by establishing the volume remaining in placebo-controlled, randomised double-blind study the the bottle. The randomisation list was kept locked at efficacy of a standardised extract of fresh Crataegus the study coordinator of the sponsor.
berries (Rob 10) on exercise tolerance and quality oflife has been shown (Rietbrock et al. 2001). Earlier, an Patients
observational study in 44 patients using an extract of Patients were recruited from 12 centres (10 internists fresh Crataegus berries (Crataegisan®) showed a clini- and 2 general practitioners) in Germany. They were be- cally significant improvement in symptoms in 86% of tween 44 and 79 years of age (median value: 65 years, patients and a very good tolerability (Degenring, mean value: 64.8 years) with NYHA class II heart fail- 1996). The current study is a controlled, randomised ure diagnosed at least three months previously and able trial to evaluate the efficacy and safety of Crataegisan® to undergo a bicycle exercise test. Ejection fraction on in heart failure to be conducted in accordance with the echocardiography was at least 45% with no subsequent guidelines of Good Clinical Practice (GCP).
changes in clinical condition. Concomitant medica-tions were not allowed during the study and within 4weeks before the study. Pregnant females and those of ᭿ Methods
childbearing age not using adequate contraceptionwere excluded as were patients with a history of drug Study design
or alcohol abuse, psychiatric illness or those having The study is a double-blind, placebo controlled, ran-domised, parallel group, multicentre trial in patientswith cardiac failure of NYHA Class II. At visit 1 (Day Table 1. Exercise test discontinuation criteria.
0), patients who had given written informed consent toentry were checked for eligibility. Demographic de- tails, medical history, cardiac symptoms and concomi- tant medication were recorded. An echocardiogram was performed, if one had not been done within the ST depression more than 4 mm (1 mm = 0.1 mV) Exercise tolerance was determined by bicycle er- Drop in systolic blood pressure of more than 15 mm Hg com- gometry. The test was started with a load of 25 watts and this was increased by 25 watts every two minutes A randomised double blind placebo controlled clinical trial of Crataegus berries taken part in a clinical trial within the previous 30 days.
plus 12.5 watts. The primary variable for the evaluation Patients with anaemia, thyroid disease, obstructive dis- of efficacy was the change in exercise tolerance be- eases of the respiratory tract, malignant tumour or hep- tween baseline (visit 1) and the final visit (visit 3).
atic or renal insufficiency were not eligible. Secondary variables included the blood pressure- A number of cardiac pathologies were excluded and heart rate product (BHP), calculated as (systolic BP × some concomitant medications were not permitted heart rate/100) at 50 watts and at the maximum wattage within the previous four weeks (Table 2). attained by the patient at visit 1 and visit 3. BHP hasbeen used as parameter in older studies and therefore, Treatment
has been included here. The reduction of BHP shows a The active study medication was an ethanolic (49% linear proportionality to the reduction of myocardial V/V) extract (DER 1:3.2) of fresh Crataegus oxyacan- tha L. et monogyna Jacq. (Crataegisan®, Bioforce). A Subjective cardiac symptoms at rest (sensations of dose of 0.75 ml (30 drops) diluted in water was to be pressure/constriction, palpitations, nervousness, stab- taken orally half an hour before meals, three times bing pain, quick pulse, feelings of unrest) and at high- daily. This resulted in a daily dose of the active er levels of exertion (fatigue, dyspnoea, cough, angi- oligomeric procyanidines of at least 6.4 mg or total nal symptoms, palpitations) were assessed by the pa- phenolic compounds of at least 12.7 mg. The placebo tient on a categorical rating scale as none, mild, mod- medication was coloured drops containing no Cratae- erate or severe. With milder degrees of severity such gus. The active and placebo medications were identical as NYHA class II, symptoms at rest are usually not in appearance, odour and taste. Treatment was sched- heart specific, however, should not be left out of ac- uled to continue for 56 (± 7) days.
An overall assessment of efficacy at the final visit Study measurements
was provided by the patient and the investigator. • Efficacy: Exercise tolerance testing is an important di-agnostic and prognostic tool for assessing patients with • Safety: Safety was assessed by the recording of all suspected or known ischiemic heart disease. It is among adverse events during the study, patient and investiga- the cardiologically approved methods for evaluation of tor evaluation of tolerability and patient evaluation of efficacy of cardiac medications (Schmidt et al. 1994).
acceptability of the treatment. There were no safety Exercise tolerance was defined as the maximum wattage that was sustained for 2 minutes during bicycleexercise testing. If the wattage at which the exercise test Statistical analysis and Sample size
was discontinued was sustained for at least 1 minute, The individual and summary evaluations of patient the exercise tolerance was the previous wattage level data were performed with SAS, version 6.12. Test anal-yses were carried out with TESTIMATE, version 5.2.
The main criterion for the assessment of efficacy was Table 2. Study exclusion criteria.
the change in exercise tolerance from baseline (visit 1)to visit 3 in the intention to treat (ITT) population (all patients randomised). Comparison between the activeand placebo groups was by the two-way U-test (Mann- Whitney Rank sum Test). Primary analysis was per- formed on the ITT – population, missing values of the main criterion were replaced by the last observation The statistical analysis was carried out without strat- ification because the number of patients in most of the Sample size calculations were based on an estimated difference in the relative reduction of exercise toler- ance between active and placebo of 0.10 and a standard deviation of 0.16. Sixty one patients were required ineach group to have a 90% power of detecting a signifi- cant difference between active and placebo medicationat the 5% level, using two-tailed tests. Assuming a withdrawal rate of 12% a total of 140 patients were re- ᭿ Results
higher levels of exertion were also similar. The meanpercentage treatment compliance was over 90% in both A total of 143 patients were recruited by 12 centres.
Two centres recruited more than 25 patients, four cen-tres between twelve and sixteen patients and six centres Efficacy
one to seven patients. These 143 patients comprise theITT population. Three patients withdrew from treat- In the ITT population there was an increase in exercise ment at their own request (2 from verum, 1 from place- tolerance in both groups between visit 1 and visit 3 bo) and 140 patients completed the study. There were (Table 4, Fig. 2). The difference between the treatment 23 patients with protocol violations (12 violations in groups was 8.3 watts in favour of Crataegisan® and this the verum and 16 in the placebo group), mainly due to was statistically significant (Mann-Whitney statistic medication compliance being less than 70%, and these 0.596, 95% confidence interval –16.3 to –0.3, p = 0.045).
were excluded from the analysis of the per protocol The result is confirmed in the PP population where there was a treatment difference of 9.5 watts in favour The two groups were similar in terms of demograph- ics and baseline clinical signs (Table 3). Exercise toler- There were no statistically significant differences be- ance and subjective cardiac symptoms at rest and at tween the two groups for changes in blood pressureheart rate product (BHP) at a load of 50 watts or at themaximum load achieved or in depression of the STsegment on ECG (Table 5). The subjective assessment of cardiac symptoms at rest and at higher levels of exertion did not change sig-nificantly. A detailed listing of the symptoms at exer-tion is given in Table 6.
The patient and investigator overall assessment of efficacy was similar for the two groups. 72.4% of thepatients considered the preparation to have an averageto good efficacy (placebo 62.2%).
Nine patients in the Crataegisan® group and 11 patientsin the placebo group reported adverse events. Thesewere gastrointestinal, musculoskeletal, respiratory, uri-nary, vascular and psychiatric disorders of mild to mod- Table 3. Patients baseline characteristics as number. Height,
weight and ejection fraction expressed as mean value (SD).
Fig. 1. Flow diagram of the clinical trial.
A randomised double blind placebo controlled clinical trial of Crataegus berries erate severity. All were assessed by the treating physi- pliance with the requirements of GCP to investigate the cians as being unlikely related to the study medication.
effects of an extract of Crataegus berries in patients with The tolerability of both the study medication and place- mild heart failure (Rietbrock et al. 2001). The daily dose bo were assessed as ‘good’ by 98.6% of patients. A sim- of Crataegus berries extract (DER 1:3.2) of 2.25 ml cor- ilar number of patients in the two groups would take the responding to at least 6.4 mg oligomeric procyanidines medication again (82.6% active, 87.8% placebo). per day is lower than that in other clinical studies(160–900 mg of flowers and leaves extract DER 4–7:1per day containing 18.75% oligomeric procyanidines).
᭿ Discussion
However, a similar degree of improvement in the exer-cise tolerance was found using extracts from leaves and This is to our knowledge the second randomised, dou- flowers of the plant (Eichstädt et al. 1989; Förster et al.
ble-blind, placebo controlled study carried out in com- 1984; Schmidt et al. 1994; Tauchert et al. 1994; Zapfe jun., 2001). In the majority of pub-lished studies the duration of treat- Table 4. Change in Exercise tolerance expressed in watt
ment is eight weeks. Two studies offour weeks of treatment produced –––––––––––––––––––––––––––––––––––––– –––––––––––––––––––––––––––––––––––––––– städt et al. 1989). A treatment dura-tion of 12 weeks produced similar re- Table 5. Changes in other parameters of efficacy.
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– * Differences between visit 3 and visit 1 were calculated only from patients who completed these two visits Fig. 2. Change in Exercise tol-
erance after 28 and 56 days of
treatment with a standardised
extract of fresh berries of
Crataegus oxyacantha L and
monogyna Jacq. (Crataegisan®)
or placebo in the ITT popula-
tion (n = 143). The difference
between the groups was 8.3
watts in favour of the extract
(p = 0.0453).
Table 6. Subjective symptoms at higher levels of exertion on day 0 and day 56.
occur until a significantlyhigher wattage has been cycle ergometry allows theconclusion that NYHA II pa- Crataegus berry extract. Theimpact of treatment and hence mortality significantly (Rogeret al. 1998). Further research is nificant. Similar results havebeen seen in other studies increase in exercise tolerancein patients with congestive extract combinations ofCrataegus flowers and leaves.
᭿ References
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keit des Herzens mit Crataegisan®. N Schweiz Zschr WHO monograph, Draft 2: Folium cum Flore Crataegi. Eichstädt H, Bäder M, Danne O, Kaiser W, Stein U, Feslix R (1989) Crataegus-Extrakt hilft dem Patienten mit NYHA- Zapfe jun. G (2001) Clinical efficacy of Crataegus extract II Herzinsuffizienz Therapiewoche 39: 3288–3296 WSR 1442 in congestive heart failure NYHA class II. Phy- Förster A, Förster K, Bühring M, Wolfstädter HD (1984) Crataegus bei mäßig reduzierter linksventrikulärerAuswurffraktion. Münch med Wschr 136 (Suppl 1): 21–26 Leuchtgens H (1993) Crataegus-Spezialextrakt WS 1442 bei ᭿ Address
Herzinsuffizienz NYHA II. Fortschr Med 111: 352–354 Rietbrock N, Hamel M, Hempel B, Mitrovic V, Schmidt T, Wolf GK (2001) Wirksamkeit eines standardisierten Ex- A. Suter, Bioforce AG, Abt. Medizin, Postfach 76, traktes aus frischen Crataegus-Beeren auf Belastungstoler- anz und Lebensqualität bei Patienten mit Herzinsuffizienz Tel.: +41 71 4546 203; Fax: +41 71 4546 164 (NYHA II). Arzneim-Forsch/Drug Res 51 (II) 793–798

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