Download The efficacy and safety of Crataegus extract WS® 1442 in patients

European Journal of Heart Failure 10 (2008) 1255 – 1263
www.elsevier.com/locate/ejheart
The efficacy and safety of Crataegus extract WS® 1442 in patients with
heart failure: The SPICE trial
Christian J.F. Holubarsch a,⁎, Wilson S. Colucci b , Thomas Meinertz c ,
Wilhelm Gaus d , Michal Tendera e
on behalf of the Survival and Prognosis: Investigation of Crataegus Extract WS® 1442 in CHF
(SPICE) trial study group
a
Median Clinics Bad Krozingen, Bad Krozingen, Germany
Cardiology Department, Boston Medical Center, Boston, USA
Department of Cardiology/Angiology, University Medical Center , Hamburg-Eppendorf, Hamburg, Germany
d
Department of Biometrics and Medical Documentation, University of Ulm, Ulm, Germany
e
3rd Division of Cardiology, Medical University of Silesia, Katowice, Poland
b
c
Received 27 February 2008; received in revised form 7 July 2008; accepted 9 October 2008
Abstract
Background: Crataegus preparations have been used for centuries especially in Europe. To date, no proper data on their efficacy and safety as
an add-on-treatment are available. Therefore a large morbidity/mortality trial was performed.
Aim: To investigate the efficacy and safety of an add-on treatment with Crataegus extract WS® 1442 in patients with congestive heart failure.
Methods: In this randomised, double-blind, placebo-controlled multicenter study, adults with NYHA class II or III CHF and reduced left
ventricular ejection fraction (LVEF ≤ 35%) were included and received 900 mg/day WS® 1442 or placebo for 24 months. Primary endpoint
was time until first cardiac event.
Results: 2681 patients (WS® 1442: 1338; placebo: 1343) were randomised. Average time to first cardiac event was 620 days for WS® 1442
and 606 days for placebo (event rates: 27.9% and 28.9%, hazard ratio (HR): 0.95, 95% CI [0.82;1.10]; p = 0.476). The trend for cardiac
mortality reduction with WS® 1442 (9.7% at month 24; HR: 0.89 [0.73;1.09]) was not statistically significant (p = 0.269). In the subgroup
with LVEF ≥ 25%, WS® 1442 reduced sudden cardiac death by 39.7% (HR 0.59 [0.37;0.94] at month 24; p = 0.025). Adverse events were
comparable in both groups.
Conclusions: In this study, WS® 1442 had no significant effect on the primary endpoint. WS® 1442 was safe to use in patients receiving
optimal medication for heart failure. In addition, the data may indicate that WS® 1442 can potentially reduce the incidence of sudden cardiac
death, at least in patients with less compromised left ventricular function.
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Crataegus extract WS® 1442; Congestive heart failure; Survival; Efficacy; Safety; Controlled randomised trial
1. Introduction
⁎ Corresponding author. Median Kliniken Bad Krozingen, HerbertHellmann-Allee 38, 79189 Bad Krozingen, Germany. Tel.: +49 7633
936871; fax: +49 7633 936872.
E-mail address: [email protected] (C.J.F. Holubarsch).
Hawthorn extracts are used world-wide as a herbal
remedy for the treatment of cardiovascular diseases and in
particular heart failure. One such product is WS® 1442,1 a
1
Manufactured by Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe,
Germany.
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2008.10.004
1256
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
dry extract from hawthorn leaves with flowers (4–6.6:1),
extraction solvent: ethanol 45% (w/w), adjusted to a content
of 17.3-20.1% of oligomeric procyanidins. In a number of
European countries, this drug has been registered as a
phytopharmaceutical medicinal product for the treatment of
early stages of congestive heart failure corresponding to
stage II of the New York Heart Association (NYHA)
classification. This is in contrast to several other hawthorn
products of different quality and composition, which are
mainly available as nutraceuticals.
Besides oligomeric procyanidins, WS® 1442 contains
mainly flavonoids (flavones, flavonols), including hyperoside, vitexin-rhamnoside, rutin, and vitexin as well as
triterpenoids and phenol carboxylic acids [1]. As may be
expected by the complex mixture of constituents, WS® 1442
has been observed to interact with multiple pharmacological
targets. In vitro experiments with human cardiac tissues have
demonstrated a concentration-dependent increase of myocardial contractility which was accompanied by a transient
raise in intracellular calcium. This positive inotopic effect is
possibly mediated by a cAMP-independent inhibition of
Na+/K+-ATPase and goes along with an improved energy
turnover of myocytes [2–5]. In contrast to cardiac glycosides, Crataegus extract has been found to prolong both the
action potential and the refractory period and thereby possess
pronounced anti-arrhythmic properties [2,4,6]. Recently, it
has been described that WS® 1442 causes vasorelaxation by
an endothelium-dependent and NO-mediated mechanism via
eNOS-phosphorylation at serine 1177 [7]. In animal models
of ischaemia and reperfusion, a significant reduction of
ventricular fibrillation, tachycardia, area of infarction and
rate of mortality has been observed. An increased coronary
blood flow as well as reduced endothelial dysfunction,
inhibition of lipid oxidation and anti-inflammatory properties may contribute to these cardioprotective effects of WS®
1442 [8,9].
In clinical trials, the intake of WS® 1442 was associated
with an improved exercise capacity and decreased heart
failure symptoms [10–13]. The combination of a positive
inotropic effect and mild vasodilation may explain the
increase in ejection fraction observed in heart failure patients
following treatment with Crataegus extract [14,15].
Previous clinical studies investigating the efficacy of
WS® 1442 in patients with congestive heart failure in NYHA
class II [10,11,13,16] or III [12] confirmed the efficacy of the
herbal extract in chronic heart failure during short-term and
long-term administration [17]. However, these studies used
left ventricular ejection fraction (LVEF), double product
(heart rate × systolic blood pressure × 10− 2), or exercise
tolerance as the primary outcome measure for efficacy, and
their protocols restricted concomitant cardiac medication.
Typically, patients with more severe forms of congestive
heart failure, who suffer from a marked impairment of left
ventricular function, are stabilized on an individually titrated
combination of several drugs, the most important of which
are β-blockers, angiotensin converting enzyme inhibitors,
angiotensin-II-receptor-antagonists, diuretics, and digitalis.
Other compounds that increase intracellular cyclic AMP
levels tend to improve symptoms of congestive heart failure,
but may increase mortality rate [18–21]. Up to now, WS®
1442 has not been studied in this clinical environment.
We report the results of the SPICE (Survival and
Prognosis: Investigation of Crataegus Extract WS® 1442
in congestive heart failure) study, which was conducted as a
morbidity and mortality trial in patients with chronic heart
failure in NYHA functional class II or III and at least
moderately impaired left ventricular function despite optimal
treatment with an individually titrated regimen of any
combination of medically appropriate drugs. The study
thus investigated the efficacy of adjunctive WS® 1442 in
reducing mortality and morbidity beyond the effect of the
treatment considered optimal for the individual patient by the
investigator.
2. Methods
2.1. Protocol and design, objectives
A detailed description of the design, objectives and
experimental procedures has been published elsewhere [22].
SPICE was performed as a double-blind, randomised,
placebo-controlled, multicenter trial performed in 13 European countries. The primary objective of the trial was to
assess the efficacy and safety of Crataegus Extract WS®
1442 administered in addition to standard medication in
patients suffering from symptoms of NYHA class II-III
congestive heart failure despite appropriate, individually
titrated treatment. Following a 4-week, single-blind placebo
run-in phase, eligible patients were randomised and received
the investigational treatment or matching placebo for a
period of up to 24 months with follow-up visits scheduled
every 3 months.
The study protocol was reviewed and approved by the
appropriate independent ethics committees. All participants
provided written informed consent. The principles of Good
Clinical Practice and the Declaration of Helsinki were
adhered to.
2.2. Participants
Male and female out-patients were recruited. Participants
had to be at least 18 years old and had to present with clinical
signs and symptoms of chronic heart failure, NYHA class II
or III, due to ischaemic heart disease, idiopathic dilated
cardiomyopathy, or hypertensive heart disease with left
ventricular dilatation. A wall motion index ≤1.2 (corresponding to a LVEF ≤ 35%) determined by transthoracic 2Dechocardiography in a certified central laboratory was
required for randomization. Furthermore, eligible patients
had to have an exercise time between 2 and 12 min in
symptom limited bicycle exercise tests (starting at 25 W
workload, with a workload increase of 25 W every 2 min) at
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
both screening and baseline, with the difference between
both visits not exceeding 1 min. There were no restrictions
regarding ethnic groups.
Patients suffering from chronic heart failure attributable
to haemodynamically significant valvular disease, with a
history of cardiac arrest or symptomatic sustained ventricular
tachycardia not adequately controlled by drugs or implantation of a defibrillator, were excluded. Other conditions that
led to exclusion were sick-sinus-syndrome, 2nd or 3rd
degree AV block not controlled by a pacemaker, congenital
heart disease, hypertrophic or restrictive cardiomyopathy,
left ventricular hypertrophy without dilatation, myocardial
infarction, unstable angina, or cardiac surgery within
3 months before study inclusion, peripheral arterial disease
symptomatic at rest, as well as chronic obstructive
pulmonary disease. Patients with planned surgical or nonsurgical cardiac intervention during the treatment period as
well as those with diseases that might interfere with the study
procedures (e. g., with the bicycle exercise test), or with
inadequately controlled insulin dependent diabetes mellitus
or arterial hypertension were not eligible for participation.
2.3. Interventions, blinding
WS® 1442 is a dry extract from hawthorn leaves with
flowers (4–6.6:1), extraction solvent: ethanol 45% (w/w). The
extract is adjusted to 17.3–20.1% oligomeric procyanidins.
Film-coated tablets containing 450 mg of the extract were used.
Film coated placebo tablets were identically matched. During
the double-blind, randomised treatment period the patients had
to take 2 film-coated tablets per day corresponding to 900 mg/
day of dry extract in case of WS® 1442. β-Blockers,
angiotensin converting enzyme (ACE) inhibitors, diuretics,
and digoxin or digitoxin were permitted as concomitant
medication in any clinically appropriate combination or dose.
However, concomitant intake of other Crataegus extract
preparations, calcium channel blockers, angiotensin-II-receptor antagonists (except in patients with intolerance to ACE
inhibitors), or class-I-antiarrhythmics was not allowed.
2.4. Outcomes
The primary outcome measure for treatment efficacy was
the number of days between baseline and the first cardiac
event, defined as a composite of cardiac death (sudden
cardiac death, death due to progressive heart failure, fatal
myocardial infarction), non-fatal myocardial infarction, or
hospitalization due to progressive heart failure. Sudden
cardiac death was defined as death without warning or within
1 h of symptoms. This composite endpoint was chosen under
consideration of the many potential mechanisms of action of
Crataegus extract. Secondary efficacy outcome measures
included each individual endpoint contributing to a cardiac
event, workload during exercise testing, echocardiographic
measures, as well as quality of life and pharmacoeconomic
assessments. The assessments of safety and tolerability were
1257
based on spontaneous reports of adverse events (AEs) and
routine laboratory measurements. Adverse events were
closely monitored by an independent Data Safety and
Monitoring Committee (DSMC); an independent Critical
Event and Endpoint Committee assessed all serious adverse
events for fulfilment of the criteria for a cardiac endpoint
and, if applicable, assigned it to one of the pre-defined
endpoint categories. All echocardiography recordings were
evaluated by two certified core laboratories [22].
2.5. Random sequence generation, allocation concealment,
implementation
Patients meeting the selection criteria at baseline were
randomised at a ratio of 1:1 to WS® 1442 or placebo. The
randomization was performed in blocks stratified by trial
centre. The block size was withheld from the investigators. A
biometrician otherwise not involved in the trial, generated
the code using a validated computer program. The study
drugs were dispensed to the centres in numbered containers.
Upon inclusion into randomised treatment the local
investigator allocated each patient the lowest available
number. Breaking the code was restricted to those emergency
cases which absolutely required knowledge of patients'
treatment for medical management. In case of opening an
emergency envelope, time, date, name of the person opening
and the reason for opening were documented on the envelope
and in the corresponding CRF. All emergency envelopes had
to be returned to the biometric division to be checked up for
completeness and closure when the trial was completed.
2.6. Statistical methods, sample size
The main objective of the trial was to demonstrate superiority
of WS® 1442 over placebo in the prevention or postponement
of cardiac events. Time until first cardiac event was evaluated by
Kaplan-Meier survival analysis. The treatment groups were
compared using a log-rank test stratified for countries. As
prespecified in the protocol, this test was performed on the
intention-to-treat (ITT) analysis set which included all randomised patients to confirm the primary hypothesis. All secondary
efficacy and safety measures were exploratory, i.e. all p-values
have to be considered as descriptive.
The trial was performed according to a group sequential
design with two interim analyses that were performed by the
DSMC after occurrence of about 1/3 and 2/3 of the expected
total number of cardiac events, respectively. The members of
the DSMC were two cardiologists and a statistician who were
otherwise not involved in the trial. The global type I error
level was α = 0.05 (two-sided). According to the group
sequential boundaries of the Peto-Haybittle design [23,24]
local type I error levels of α1 = α2 = 0.001 were applied to each
interim analysis in order to reserve a level of α3 = 0.0494 for
the final analysis.
According to data from the literature [25,26] a 24-month
rate of cardiac events of approximately 30% was expected in
1258
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
the placebo group. WS® 1442 was assumed to improve the
event rate by 20%, i.e., a rate of cardiac events of about 24%
was anticipated in patients treated with the herbal extract.
Following these assumptions, 1155 evaluable patients per
group were required in order to obtain a power of 90%. Before
the first interim analysis a blinded sample size review [27] was
performed to re-assess the assumed overall rate of cardiac
events. As a result of the blinded sample size re-calculation the
initially planned sample size was increased by 230 patients to
2 × 1270 = 2540 patients to assure the desired power of 90%.
3. Results
3.1. Recruitment, participant flow
In 145 clinical centres in 13 European countries, 3601
patients were recruited and 2681 (WS® 1442: 1338; placebo:
1343) were randomised and treated. All randomised patients
were included into the ITT analysis of efficacy as well as into
the safety analysis. About 50% of the patients were recruited
in Poland, the Czech Republic and in Germany. On average
each centre recruited about 18 patients (interquartile range:
24–4). There were no centre or country effects.
3.2. Baseline data
Baseline demographic and clinical parameters were
comparable in both groups (Table 1). More than 80% of the
randomised patients were male, and about half of the
participants were 60 years of age or older. In total, 42%
(WS® 1442) and 45% (placebo) of the participants had
NYHA class III congestive heart failure. All but 6 patients
received concomitant cardioactive medication, and about
90% took at least 3 concomitant cardioactive drugs. In each
treatment group, about 85% of the patients took diuretics
(about 39% spironolactone), 83% received ACE-inhibitors,
64% were treated with β-blockers (almost one half with
carvedilol and almost one third with metoprolol), and 56%
with digitalis and nitrates. Concomitant antiarrhythmics
(mostly amiodarone) were used by about 22% of the study
participants. One subject (0.07%) in the WS® 1442 group and
5 subjects (0.37%) in the placebo group had an implantable
cardioverter-defibrillator (ICD) in place at study entry.
3.3. Investigational treatment
Across the follow-up period the interquartile range for
treatment compliance (assessed by medication counting) was
96.2%–102.3% for WS® 1442 and 96.3%–101.5% for
placebo. Disposition of patients is shown in Fig. 1.
3.4. Efficacy
Fig. 2 shows the Kaplan-Meier cumulative hazard curves
for the composite primary endpoint. The 24-month event
rates were 27.9% (373 of 1338) and 28.9% (388 of 1343) in
Table 1
Demographic and clinical characteristics at baseline (intention-to-treat;
numbers are means ± SD and medians unless stated otherwise; p-values are
two-sided)
Sex (n (%))
female
male
Age [years]
Body Mass Index [kg/m2]
Smoking (n (%))
Non-smoker
Smoker
Ex-smoker
NYHA class (n (%))
I⁎
II
III
Left ventricular ejection
fraction
(acc. to Berning; %)
at screening
WS® 1442
(n = 1338)
Placebo
(n = 1343)
p
222 (16.6%)
1116 (83.4%)
59.8 ± 10.6
60.0
27.0 ± 3.9
26.6
213 (15.9%)
1130 (84.1%)
60.4 ± 10.7
61.0
26.8 ± 3.7
26.6
0.61#
611 (45.7%)
144 (10.8%)
583 (43.6%)
621 (46.2%)
145 (10.8%)
577 (43.0%)
0.95#
3 (0.2%)
769 (57.5%)
566 (42.3%)
23.8 ± 6.8
6 (0.5%)
731 (54.4%)
606 (45.1%)
23.9 ± 6.6
0.18#
24.4
24.4
(n = 1317)
Bicycle exercise duration (s) 320.0 ± 135.8
300.0
(n = 1337)
Number of concomitant
cardioactive drugs (n (%))
none
2 (0.2%)
1 or 2
150 (11.2%)
3
331 (24.7%)
more than 3
855 (63.9%)
(n = 1323)
313.8 ± 135.2
293.0
(n = 1342)
4 (0.3%)
144 (10.7%)
359 (26.7%)
836 (62.3%)
0.15$
0.24$
0.78$
0.24$
0.55#
χ -test; $t-test.
⁎These patients had NYHA stage II at the screening visit.
# 2
the WS® 1442 and placebo groups respectively. The average
time to first cardiac event was 620 (95% confidence interval:
608; 632) and 606 (593; 619) days. The difference between
the two groups did not reach statistical significance (p = 0.51,
log rank test stratified by country).
Among the events contributing to the composite endpoint, patients treated with WS® 1442 showed a tendency
towards lower 24-month event rates than the placebo group
for death of any cause, death of cardiac cause, sudden cardiac
death, death due to progressive heart failure and non-fatal
myocardial infarction, but none of the differences reached
the level of statistical significance (Table 2).
Fig. 3A and B shows the cumulative hazard curves in
cardiac mortality and sudden cardiac death. Sudden cardiac
death accounted for 58.7% of all cases of cardiac mortality.
With WS® 1442 there was a non-significant relative reduction
in cardiac mortality by 9.7% (HR 0.89, 95% CI [0.73;1.09]);
p = 0.269) and sudden cardiac deaths by 15.4% (HR 0.84,
95% CI [0.64;1.09]; p = 0.184). Among the 2681 patients
randomised to treatment, 1139 (42.5%) had an initial left
ventricular ejection fraction between 25% and 35% (upper
limit for inclusion). In this pre-specified subgroup, cardiac
mortality in the WS® 1442 group as compared to placebo was
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
1259
Fig. 1. Disposition of patients, analysis data sets.
reduced by 20% (HR 0.78, 95% CI [0.56;1.10]); p = 0.158),
with a significant reduction in sudden cardiac deaths by
39.7% (HR 0.59, 95% CI [0.37;0.94]; p = 0.025) (Fig. 3C and
D). These represent an exploratory analysis, and therefore
should be treated with caution. p-values at different timepoints are shown in Fig. 4.
frequently reported AEs were cardiac disorders (WS® 1442
group 30.3%, placebo group 30.7%), followed by metabolic
and nutritional disorders (16.5% and 17.2%, e. g., hypercholesterolaemia, hyperlipidaemia), infections (13.0% and
16.2%, e. g., influenza, bronchitis), and by general disorders
(10.2% and 11.9%, e. g., chest pain, pyrexia).
3.5. Safety/tolerability
4. Discussion
During treatment, 897 patients randomised to WS® 1442
(67.0%) reported 2196 adverse events (AEs) and 917
patients treated with placebo (68.3%) experienced 2279
AEs. This corresponded to one AE in 388 days of exposure
for WS® 1442 and to one AE in 370 days for placebo.
Serious AEs were observed in 524 patients (39.2%) in the
WS® 1442 group (873 events, one in 976 days of exposure)
and in 552 patients (41.1%) in the placebo group (923
events, one in 914 days). In both study groups the most
Congestive heart failure is among the leading causes of
death in the Western world. While ACE inhibitors, βblockers, and aldosterone receptor blockers have been shown
to reduce over-all mortality [28,29], treatment with cyclic
adenosine monophosphate increasing agents may result in a
deterioration of outcome [19,20,21]. Digoxin, on the other
hand, which is to date the only positive inotropic drug shown
to be devoid of harmful effects on mortality during long-term
treatment [5], improved exercise tolerance and quality of life
1260
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
Fig. 2. Cumulative hazard curves showing time to first cardiac event.
and reduced the need for hospitalization in heart failure
patients, but had no beneficial effect on over-all mortality
[25,30]. However, in a post-hoc analysis it was found that
lower serum digoxin concentrations are associated with
improved survival [31]. A clinically relevant reduction of the
risk of sudden cardiac death could be demonstrated for βblocking agents alone [32–34].
The efficacy of Crataegus extract WS® 1442 in improving exercise capacity and subjective symptoms was
previously demonstrated in patients with milder forms of
heart failure, with limited concomitant medication, and with
short follow-up periods between 4 and 16 weeks [10–13,16].
In the light of these facts, the SPICE study was planned
and designed to assess the effectiveness and safety of the
Crataegus extract WS® 1442 when given to patients with
more advanced heart failure, who were receiving optimal
standard pharmacological therapy. Due to the potential
mechanisms of action of Crataegus extract, we have chosen a
primary end-point composed of three components: Firstly,
the inotropic effect of WS® 1442 demonstrated in vitro was
expected to reduce hospitalization and death rate due to
progression of heart failure. Secondly, the anti-ischaemic
properties of Crataegus as demonstrated in a number of
animal models might lead to a reduction of fatal and nonfatal myocardial infarction. And thirdly, the anti-arrhythmic
and anti-fibrillatory effects of Crataegus might have an
influence on sudden cardiac death.
In the SPICE study, special care was taken to include a
very homogeneous and well defined population of patients in
order to reach the expected 24-month rate of cardiac events
of approximately 30%, and to investigate patients who
receive optimal medical treatment. This aim was reached by
introducing left ventricular ejection fraction equal to or lower
than 35% as an inclusion criterion, as assessed by a certified
central laboratory before randomization. The fact that the
patients were on optimal pharmacological treatment can be
seen from Table 1; more than 60% of the patients in both
groups had four or more, and almost 90% had at least three
concomitant cardioactive drugs at baseline.
For the composite primary endpoint that included cardiac
death, non-fatal myocardial infarction and hospitalization
due to progressive heart failure, confirmatory proof of
efficacy of WS® 1442 was not achieved. Crataegus extract
did not reduce the need for hospitalization due to progression
of heart failure, the most frequently reported event
contributing to the composite endpoint. The same was true
for death due to progression of heart failure. However, WS®
1442 tended to lower sudden cardiac death rate, which was
particularly pronounced in patients with an LVEF between
25% (approximate median of all randomised patients) and
35% (upper limit for inclusion). These findings illustrate
potential anti-arrhythmic and/or anti-ischaemic properties of
Crataegus extract WS® 1442. In this context it is noteworthy
that the prevalence of implantable cardioverter defibrillator
(ICD) therapy was very low. Although the lack of effect on
pump failure related endpoints was unexpected, the antiarrhythmic action of WS® 1442 confirms the findings from
animal experiments, in which it was shown to effectively
prevent reperfusion arrhythmias.
Both digoxin and WS® 1442 are known to increase
exercise capacity. However, WS® 1442, with its tendency to
reduce sudden cardiac death rate, may have a more
favourable safety profile than digoxin.
In the SPICE trial, administration of WS® 1442 was
associated with an excellent safety and tolerability profile.
The adverse events observed during treatment with WS®
1442 were of the same types and occurred at comparable
rates as those in the placebo group. Of note, despite the
positive inotropic effect of Crataegus extract preparations
[2,35] observed in vitro, WS® 1442 did not lead to an
increase in mortality rate. In contrast, a tendency for
reduction of cardiac mortality was observed.
In a recent systematic review based on data from 24
controlled clinical studies with Crataegus preparations and
Table 2
Mortality and morbidity after 24 months follow-up (intention-to-treat;
number (%) of patients and two-sided log rank test p-value)
Death (any cause)
Death of cardiac cause
Sudden cardiac death
Death due to progressive heart
failure
Fatal myocardial infarction
Non-fatal myocardial infarction
Hospitalization due to progression of
heart failure
Total no. of patients with cardiac
event
WS® 1442
(n = 1338)
Placebo
(n = 1343)
p
219 (16.4)
180 (13.5)
102 (7.6)
64 (4.8)
240 (17.9)
200 (14.9)
121 (9.0)
69 (5.1)
0.29
0.27
0.18
0.63
14 (1.0)
13 (1.0)
253 (18.9)
10 (0.7)
21 (1.6)
245 (18.2)
0.43
0.15
0.78
373 (27.9%)
388 (28.9%)
0.51
Numbers of individual events do not sum up to total as some patients had
multiple events.
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
1261
Fig. 3. Cumulative hazard curves for cardiac mortality (A, C) and sudden cardiac death (B, D) — all patients (A, B) or patients with LVEF ≥ 25% (C, D).
Fig. 4. Cardiac mortality and sudden cardiac death in total population and subgroup LVEF ≥ 25%. Plot shows hazard ratios and 95% confidence intervals.
All p-values are explorative. They are computed by two-sided log rank tests.
1262
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
more than 5500 patients analyzed, Daniele and colleagues
[36] emphasized a good tolerability of the herbal extract and
the absence of drug interactions (that is particularly
important in patients receiving multiple drugs). The results
of the SPICE trial are in line with this meta-analysis.
In conclusion, add-on treatment with WS® 1442 to a
conventional heart failure regimen did not show a significant
difference in the composite endpoint including cardiac death,
non-fatal myocardial infarction and hospitalization due to
progressive heart failure. Analysis of the secondary outcomes may suggest that WS® 1442 can reduce sudden
cardiac death in patients with LVEF between 25 and 35%.
Because WS® 1442 was well tolerated and had an excellent
safety profile, the results of this study suggest that further
exploration of WS® 1442 in patients with heart failure at
high risk for sudden cardiac death may be warranted.
Acknowledgments
We thank all the patients, physicians, nurses, and Clinical
Research Associates who collaborated in the study. We are grateful
to Prof. Dr M. Kieser for statistical help, Dr M. Niestroj for data
management, Mrs. A. Wassmer and Mrs. S. Elis for coordination of
the clinical trial sites, Mrs. P. Funk for medical writing, and Dr S.
Köhler and Dr F.A. Malek for the management of the clinical trial
on behalf of the sponsor. The study was sponsored and study
medication was provided by Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany.
Appendix
Trial organization — SPICE Trial Study Group
Steering Committee — W. S. Colucci, Boston (USA), W.
Gaus, Ulm (Germany), Ch. Holubarsch, Principal Investigator, Freiburg (Germany), Th. Meinertz, Hamburg (Germany), M. Tendera, Katowice (Poland)
Data and Safety Monitoring Committee — R. Čerbák,
Brno (Czech Republic), W. Köpcke, Münster (Germany), B.
Maisch, Marburg (Germany)
Endpoint Committee — J. Eha, Tallinn (Estonia), F. X.
Kleber, Berlin (Germany), V. Regitz-Zagrosek, Berlin
(Germany)
Investigators and Centres — Bulgaria: N. Dimov, Sofia;
R. Kermova, Pleven; N. Ivanova Konyarova, Burgas; T.
Manolova, Bankya; B. Rangochev, Varna; P. Solakov,
Plovdiv; Czech Republic: L. Ballek, Jindřichův Hradec; M.
Brtko, Hradec Králové; J. Carda, Třebíč; V. Drápalík, Nové
Mĕsto na Moravĕ; J. Dražka, Ústí nad Labem; P. Franc,
Pardubice; O. Hejhal, Kromĕříž; J. Toman, J. Krejčí, Brno; P.
Kvásová, Frýdek-Místek; P. Lang, Liberec 1; K. Peterka,
Praha 6; J. Popelová, Praha 5; J. Rybka, Zlín; Germany: V.
Adelberger, Dresden; A. Al-Zoebi, Wermsdorf; S. Albrecht,
Dresden; K. Ammer, Dresden; G. Bachour, Ahlen; A. Barth,
Königsbrück; M. Bock, Chemnitz; G. Böhm, Ludwigshafen;
H. Böneke, Lienen-Kattenvenne; H. Bründermann, Bergkamen; H.J. Busse, Halle; H. Damaschke, Wahlstedt; K. Diehl,
Ilbesheim; S. Fischer, Leipzig; R.G. Fuchs, Hermaringen; J.
Gärtner, Leisnig; S. Gaydov, Schwerin; S. Geßner, Jena; Th.
Giehrl, Bargteheide; D. Glatzel, Hannover; S. Haufe, Rastatt;
W. Heepe / P. Fries, Berlin; C.-J. Heydenreich, Essen; R.
Henke, Leipzig; L. Hennig, Berlin; M. Hilbert, Bredstedt; U.
Hofmann, Chemnitz; H. Hohensee, Dresden; M. Holzapfel,
Puchheim; F.M. Isbruch, Castrop-Rauxel; T. Jung/N. Jung,
Deggingen; S. Kaspari, Lüneburg; R. Kemper, München; K.
Kleinertz, Chemnitz; J. Krehbiel/R. Kern, RödersheimGronau; R. Kuhnen, Selm; M. Leicht, Eilenburg; S. Leszke,
Preetz; E. Lohr, Essen; M. Maas, Heidenau; W. Mandlik,
Attenkirchen; B. Nabel, Augsburg; M. Orlowski, Wahlstedt;
G. Overmeyer, Ibbenbühren; M. Pahl, Berlin; T. Peterhansl,
Berlin; R. Pospiech / B. Wille, Berlin; P. Rapp, Bergkamen;
F. Richard, Erfurt; G. Ringwald, Bruchsal; B. Ritter,
Emmendingen; W.D. Rudroff, Essen; Th. Scheibner, Ebersbach; W. Schlauch, Lochham; A. Schröder, Greven; D.
Schwarz , Apensen; W. Schwarz , Adendorf; W. Türk, Jena;
H.G. Voss, Münster; W. Weiland, Hamburg; N. Kokott, Ch.
Weiler, Berlin; J. Weimer, Reinfeld; M. Weingart, Lüneburg;
H.W. Wozny, Hamburg; K. Younossi, Ulm; R. Zotz, Leipzig;
Hungary: I. Édes, Debrecen; Latvia: A. Gozīte, Rīga; A.
Pomere, Rīga; Lithuania: J.-E. Marcinkevicienė, M.-R.
Babarskienė, Kaunas; A. Baltuškevičius, Kaunas; E. Berūkštis, Vilnius; A. Dambrauskaitė, Šiauliai; L. Jankauskienė,
Kaunas; J. Misiūra, Vilnius; A. Šimaitis, Klaipėda; R.
Steponėnienė, Vilnius; A. Valiulis, Klaipėda; L. Valius,
Kaunas; Netherlands: L.H.J. van Kempen, ZA Velp; Poland:
P. Achremczyk, Radom; M. Cholewa, Warszawa; J.
Dubejko, Lublin; M. Janion, Kielce; K. Jaworska, Toruń;
J. Kastelik, Bielsko-Biała; A. Kleinrok, Zamość; M. KrauzeWielicka, Z. Majer, Ruda Śląska; M. Krzemińska-Pakuła,
Łódź; B. Kuśnierz, Bytom; J. Kuźniar, Rzeszów; K. ŁobozGrudzień, Wrocław; W. Musiał, Białystok; E. Nartowicz,
Bydgoszcz; W. Pluta, Opole; A. Pluta , Rzeszów; L.
Poloński, Zabrze; M. Tendera, Katowice; T. Zaleska,
Warszawa; Portugal: J.A. Coucello, Portimao; SerbiaMontenegro: S. Ilić, Niška Banja; M. Kovač, Novi Sad;
D.C. Kovačević, Novi Sad; Z. Mijailović, Belgrade; M. Mirić,
Belgrade; V. Obradović, Belgrade-Zemun; M.C. Ostojić,
Belgrade; P.M. Seferović, Belgrade; Z. Vasiljević, Belgrade;
M. Zdravković, Belgrade; Slovakia: I. Gonos, Rožňava; P.
Kmeč, Banská Bystrica; D. Pella, Košice; P. Tóth, Komárno;
M. Zima, Nové Zámky; Slovenia: M. Bombek, Maribor; D.
Kovač, Murska Sobota; P. Rakovec, Ljubljana; F. ŠkrablMočnik, Celje; A. Žemva, Ljubljana; Ukraine: A. Dyadyk,
Donetsk; G.V. Dzyak, Dniepropetrovsk; V.M. Kovalenko,
Kiev; M. Lutay, Kiev; A. Parkhomenko, Kiev; S.S. Pavlyk,
Lviv; S. Polivoda, Zaporozhye; L.G. Voronkov, Kiev.
References
[1] Busse WR, Juretzek W, Koch E. Hawthorn (crataegus). In: Coates P,
Blackman MR, Cragg G, et al, editors. Encyclopedia of dietary
supplements. New York: Marcel Dekker; 2005. p. 337–47.
[2] Joseph G, Zhao Y, Klaus W. Pharmakologisches wirkprofil von
crataegus-extrakt im vergleich zu epinephrin, amrinon, milrinon und
C.J.F. Holubarsch et al. / European Journal of Heart Failure 10 (2008) 1255–1263
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
digoxin am isolierten, perfundierten meerschweinchenherzen. Arzneimittelforschung 1995;45:1261–5.
Pöpping S, Fischer Y, Kammermeier H. Crataegus-wirkung auf
konzentration und o2-verbrauch isolierter herzzellen. Munch Med
Wochenschr 1994;136:39–46.
Pöpping S, Rose H, Ionescu I, Fischer Y, Kammermeier H. Effect of a
hawthorn extract on contraction and energy turnover of isolated rat
cardiomyocytes. Arzneimittelforschung 1995;45:1157–61.
Schwinger RH, Pietsch M, Frank K, Brixius K. Crataegus special
extract ws 1442 increases force of contraction in human myocardium
camp-independently. J Cardiovasc Pharmacol 2000;35:700–7.
Müller A, Linke W, Zhao Y, Klaus W. Crataegus extract prolongs
action potential duration in guinea-pig papillary muscle. Phytomedicine 1996;3:257–61.
Brixius K, Willms S, Napp A, et al. Crataegus special extract ws 1442
induces an endothelium-dependent, no-mediated vasorelaxation via
enos-phosphorylation at serine 1177. Cardiovasc Drugs Ther
2006;20:177–84.
Chatterjee SS, Koch E, Jaggy H, Krzeminski T. In vitro and in vivo
investigations on the cardioprotective effects of oligomeric procyanidins in a crataegus extract from leaves with flowers. Arzneimittelforschung 1997;47:821–5.
Eichstädt H, Bäder M, Danne O, et al. Crataegus-extrakt hilft
bei patienten mit nyha ii-herzinsuffizienz. Therapiewoche 1989;39:
3288–96.
Leuchtgens H. Crataegus-spezialextrakt ws 1442 bei herzinsuffizienz
nyha ii. Fortschr Med 1993;111:352–4.
Zapfe jun G. Clinical efficacy of crataegus extract ws 1442 in
congestive heart failure nyha class ii. Phytomedicine 2001;8:262–6.
Tauchert M. Efficacy and safety of crataegus extract ws 1442 in
comparison with placebo in patients with chronic stable New York
heart association class-iii heart failure. Am Heart J 2002;143:910–5.
Weikl A, Assmus KD, Neukum-Schmidt A, et al. Crataegusspezialextrakt ws 1442. Objektiver wirksamkeitsnachweis des crataegus-specialextraktes ws 1442 bei patienten mit herzinsuffizienz (nyha
ii). Fortschr Med 1996;114:291–6.
Eichstätt H, Bäder H, Daune O, et al. Crataegus-extrakt hilft bei patienten
mit nyha ii-herzinsuffizienz. Therapiewoche 1989;39:3288–96.
Weikl A, Noh HS. Der einfluss von crataegus bei globaler
herzinsuffizienz. Herz Gefäße 1992;11:516–24.
Eichstädt H, Störk T, Möckel M, et al. Wirksamkeit und verträglichkeit
von crataegus-extrakt ws 1442 bei herzinsuffizienten patienten mit
eingeschränkter linksventrikulärer funktion. Perfusion 2001;14:212–7.
Pittler MH, Schmidt K, Ernst E. Hawthorn extract for treating chronic
heart failure: Meta-analysis of randomized trials. Am J Med
2003;114:665–74.
Dies F, Krell MJ, Whitlow P, et al. Intermittent dobutamine in ambulatory
out-patients with chronic cardiac failure. Circulation 1986;74:II–38.
Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on
mortality in severe chronic heart failure. The promise study research
group. N Engl J Med 1991;325:1468–75.
1263
[20] Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral
enoximone in patients with moderate to moderately severe congestive
heart failure. Lack of benefit compared with placebo. Enoximone
multicenter trial group. Circulation 1990;82:774–80.
[21] Xamoterol Study Group. Xamoterol in severe heart failure. Lancet
1990;336:1–6.
[22] Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. Survival
and prognosis: Investigation of crataegus extract ws 1442 in congestive
heart failure (spice)-rationale, study design and study protocol. Eur J
Heart Fail 2000;2:431–7.
[23] Haybittle JL. Repeated assessment of results in clinical trials of cancer
treatment. Br J Radiol 1971;44:793–7.
[24] Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized
clinical trials requiring prolonged observation of each patient. I.
Introduction and design. Br J Cancer 1976;34:585–612.
[25] Digitalis Investigation Group. The effect of digoxin on mortality and
morbidity in patients with heart failure. N Engl J Med 1997;336:525–33.
[26] SOLVD Investigators. Effect of enalapril on survival in patients with
reduced left ventricular ejection fractions and congestive heart failure.
N Engl J Med 1991;325:293–302.
[27] Gould AL, Shih WJ. Modifying the design of ongoing trials without
unblinding. Stat Med 1998;17:89–100.
[28] CONSENSUS Trial Study Group. Effects of enalapril on mortality in
severe congestive heart failure. Results of the cooperative north
Scandinavian enalapril survival study (consensus). N Engl J Med
1987;316:1429–35.
[29] Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on
morbidity and mortality in patients with chronic heart failure. U.S.
Carvedilol heart failure study group. N Engl J Med 1996;334:1349–55.
[30] Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from
patients with chronic heart failure treated with angiotensin-convertingenzyme inhibitors. Radiance study. N Engl J Med 1993;329:1–7.
[31] Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in
mortality and hospitalization in heart failure: a comprehensive post hoc
analysis of the dig trial. Eur Heart J 2006;27:178–86.
[32] Frankenberger O, Steinberg JS. Beta-blockers and amiodarone for the
primary prevention of sudden cardiac death. Curr Cardiol Rep
1999;1:274–81.
[33] Goldstein S. Beta blockers as cardioprotective agents: part ii–focus on
prevention of sudden cardiac death. Am J Manag Care 2002;8:18–24.
[34] Rajman I, Kendall MJ. Sudden cardiac death and the potential role of
beta-adrenoceptor-blocking drugs. Postgrad Med J 1993;69:903–11.
[35] Siegel G, Casper U, Walter A, Hetzer R. Weißdorn-extrakt li 132:
Dosis-wirkungs-studie zum membranpotential und tonus menschlicher
koronararterien und des hundepapillarmuskels. Munch Med
Wochenschr 1994;136(Suppl):47–56.
[36] Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event profile of
crataegus spp.: a systematic review. Drug Saf 2006;29:523–35.