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Baseline severity but not gender modulates quantified Crataegus extract effects in early heart failure - a pooled analysis of clinical trials.

ABSTRACT

Objective: The efficacy of quantified Crataegus extract in chronic heart failure (CHF) has been assessed in numerous clinical studies. The present pooled analysis evaluates the impact of baseline severity and gender on objective and patient-reported endpoints and associations between both types of outcomes in patients with early CHF.

Methods: Available data from 687 individual patients treated with quantified Crataegus extract or placebo in ten studies were pooled. Treatment effects on physiologic outcome parameters and on symptoms were analysed for their association with baseline severity and gender. Changes in symptom scores were investigated with respect to their relation to physiologic outcome parameters. Results were compared with observations in a 3-year cohort study.

Results: Physiologic outcome parameters maximal workload (MWL), left ventricular ejection fraction (LVEF) and pressure-heart rate product increase (PHRPI) at 50 W ergometric exercise improved more in active treatment than in placebo patients. Magnitude of improvement was independent from baseline for LVEF but increased for MWL and PHRPI with baseline severity. Improvement of typical symptoms like reduced exercise tolerance, exertional dyspnea, weakness, fatigue, and palpitations improved more with active treatment and in patients with more severe symptoms. A weak association between improvements in MWL, PRHP, and symptoms could be demonstrated. Gender differences in treatment effects could be explained by baseline differences. Results of the pooled analysis are in agreement with observations in the cohort study.

Conclusions: Crataegus extract treatment effects on physiologic outcomes and typical symptoms were modulated by baseline severity. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart-failure.

[c] 2011 Elsevier GmbH. All rights reserved.

ARTICLE INFO

Keywords:

Hawthorn extract

Crataegus extract

WS[R] 1442

Heart failure

Subgroup analysis

Clinical profile

Long term

Introduction

Crataegus (hawthorn) extract is a well-established herbal remedy for relief of impaired exercise-tolerance in early chronic heart-failure (NYHA I-II) due to its positive inotropic, antiarrhythmic and vasodilating properties (Rigelsky and Sweet 2002). In 2008, a meta-analysis published by the Cochrane collaboration (Pittler et al. 2008) concluded that evidence from randomized clinical trials demonstrated superiority of hawthorn extract over placebo treatment in important physiologic outcomes: maximal workload, exercise tolerance, left ventricular ejection fraction and pressure-heart rate product. Crataegus extract also significantly improved typical symptoms of heart failure, like shortness of breath and fatigue, and general well-being as indicated by symptom scores.

Recent investigations have highlighted the influence of therapeutic improvement in physiologic parameters on patient-reported benefits, or quality of life in chronic heart failure (e.g. Dos Santos et al. 2009). Treatment benefit in certain patient subgroups, e.g. female gender seems to be limited or is unknown (Podczeck-Schweighofer and Dornaus 2006). Therefore we were interested to further characterize Crataegus treatment effects in terms of correlation between objective and subjective improvements and subgroup specificity.

The majority of hawthorn clinical trials have been performed with WS [R] 1442, 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 (manufacturer: Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe). For the present exploratory analyses, we pooled individual patient data from ten clinical trials with quantified Crataegus extract. To further validate the findings, comparable analyses were done on original data from a 3-year open label cohort study with 372 patients.

Methods

Individual patient-data were available for pooled analyses from ten published trials (Table 1). Original data of individual patients from Iwamoto et al. (1981) could not be obtained for the present analysis. O'Conolly et al. (1986, 1987) performed cross-over trials; to ensure comparability with the other trials, only data form the first treatment-phase were included in the analysis. Data from Weikl and Noh (1992) were not included, as their method for assessment of LVEF (MRI) was different from the one (scintigraphy) used in three other trials. As detailed in Table 2, the endpoints evaluated differed by trial, so the number of trials that could be pooled was lower for specific analyses.
Table 1 Overview of clinical trials with quantified
Crataegus extract evaluated.

No  Author (year)     Design(a)       Patients    % male  Mean
                                                          age
                                      V(b)  P(c)

1   Hanak and         RCT.pg           30    30      57    55
    Briickel
    (1983)

2   0*ConoIlyetal.    RCT.co           36            28    73
    (l986)

3   0*ConoHyetal.     RCT, co          36            25    74
    (1987)

4   Eichstadt etal.   OT               20     -      95    56
    (l989)(d)

5   Leuchtgens        RCT.pg           15    15      60    66
    (1993)(d)

6   Weikletal.        RCT, pg          67    69      28    65
    (1996)(d)

7   Eichstadt et al.  RCT.pg           20    20      70    65
    (2001 )(d)

8   Zapfeetal.        RCT.pg           20    20      28    62
    (2001)(d)

9   Tauchert          RCT.pg        70/69    70      32    68
    (2002)(d)

10  Eichstadt etal.   RCT.pg           40    40      76    62
    (2003)(d)

11  Eggelingetal.     OPC             372    --      30    68
    (2006)(d)

No  Author (year)           NYHA stage  Durat.      Dose
                                        (weeks)   (mg/day)

1   Hanak and Briickel        I-II        3            180
    (1983)

2   0*ConoIlyetal.            I-II        6            180
    (l986)

3   0*ConoHyetal.             I-II        6            180
    (1987)

4   Eichstadt etal.             II        4            480
    (l989)(d)

5   Leuchtgens                  II        8            160
    (1993)(d)

6   Weikletal.                  II        8            160
    (1996)(d)

7   Eichstadt et al.            II        4            480
    (2001 )(d)

8   Zapfeetal.                  II       12            240
    (2001)(d)

9   Tauchert                   III       16       900/1800
    (2002)(d)

10  Eichstadt etal.                       4            480
    (2003)(d)

11  Eggelingetal.               11      156            900
    (2006)(d)

(a) RCT=randomized, double blind, placebo-controlled trial;
co = cross-over; pg = parallel group; OT=open trial; OPC =
open prospective cohort study.
(b) Active treatment.
(c) Placebo.
(d) Crataegus extract WS [R] 1442.

Table 2 Parameters evaluated.

No.  Author (year)     MWL  LVEF  PHRPI  Symptoms

1    HanakandBriickel  X
     (1983)

2    O'Conolly et al              X      Other
     .(1986)                             (Nosie.BPRS)

3    O'Conolly et al              X      Other
     .(1987)                             (Nosie.BPRS)

4    Eichstadtetal          X
     .(1989)

5    Leuchtgens                   X      vonZerssen;
     (1993)

6    Weikletal                    X      Other
     .(1996)                             (QoL scale)

7    Eichstadtetal)         X     (X)
     .(2001

8    Zapfeetal.        X          X      von Zerssen
     (2001)

9    Taucher t         X          (X)    von Zerssen; 4
     (2002)                              typical Symptoms

10   Eichstadtetal.         X     X
     (2003)

11   Eggelingetal.     X          X      MLHF; 4
     (2006)                              typical Symptoms

MWL = maximal workload; LVEF-left ventricular ejection
fraction; PHRPI = pressure-heart rate product increase.


The following efficacy parameters were evaluated in the present analysis:

Maximal workload (MWL, Watt) was assessed as the highest level of energy output performed in bicycle ergometry, using a stepwise incremental protocol with 25 W increased every 2 min; when exercise was terminated before the end of a period, the time actually elapsed was divided by 2 min, multiplied by 25 W and added to the previous level.

Left ventricular ejection fraction (LVEF, %) was measured scintigraphically by radionuclide angiocardiography at rest and during supine cycle ergometer exercise at maximum steady state heart rate.

The pressure-heart rate product increase (PHRPI, mmHg/min) was calculated as the difference in the product of systolic blood pressure and heart rate between rest and two minutes of 50 W bicycle exercise. It is considered as indirect measure of cardiac workload and oxygen consumption.

Four cardinal symptoms of chronic heart failure (reduced physical ability, exhaustion, early fatigability, and exertional dyspnea) were rated from 0 (no symptoms) to 3 (severe) as reported by patients. Quality of life was determined by the 24 item version of the symptom list (Von Zerssen 1971).

To validate results from this pooled analysis of clinical trials against real-life clinical practice experience, comparable analyses were done with data from a 3-year open cohort study. In this study, 372 patients (261 female, 111 male) of stage NYHA II taking 900 mg/day WS[R] 1442 in addition to their standard medication were followed for three years by their treating office-based physicians. The population was characterized by a baseline resting LVEF of 49 [+ or -] 15% and a MWL of 94 [+ or -] 29 W. PHRP-values after 2 min of 50 W exercise were given as absolute data (not difference from resting values; baseline 171 [+ or -] 43 mmHg/min), symptoms and quality of live were documented by the 21 item Minnesota Living with Heart Failure Questionnaire (MLHF), four cardinal symptoms (reduced physical ability, tiredness, exertional dyspnea, and palpitations) were rated from 1 (no symptoms) to 5 (severe) by investigators.

Outcome parameters were analysed for mean changes between begin and end of treatment for active treatment and placebo groups in pooled patient populations. Missing values were treated as in the original trial, i.e. LOCF (Tauchert 2002) or observed cases method (all other trials). In the cohort study, each analysis was done with data from those patients that had baseline and end of treatment values of the respective variable. In a second step, pooled populations were divided into subgroups by baseline values of the respective parameter and by gender, if sufficient patient numbers were available.

Exploratory two-sided p-values for comparisons of changes between active treatment and placebo were calculated by the Wilcoxon rank sum test. Symptom improvement in the cohort study was analysed by paired t-tests for each item and sum score. Association between baseline values and changes from baseline were analysed by means of linear regression. Associations between symptomatic improvement and change in exercise tolerance were analysed in data from Tauchert (2002) by calculating Spearman's Correlation Coefficient of MWL and von Zerssen total score as well as by comparing rate of patients with improved cardinal symptoms in the subgroups with or without improved MWL by [x.sup.2] test.

Results

Objective outcome parameters: overall efficacy and subgroup analyses

In the analysed population (3 studies, N = 306), MWL improved by 7.94 W with Crataegus extract versus 1.34W with placebo (p = 0.013). Active treatment was superior and treatment effect sizes comparable in all subgroups stratified by baseline MWL (Table 3). Absolute benefits were largest in the subgroup with poorest baseline performance, patients with better baseline MWL could be stabilized with Crataegus extract but deteriorated in the placebo group.
Table 3 Total and subgroup evaluation of pooled data,
physiologic parameters: difference final-baseline values.

Parameter (pooled       Baseline  Quantified  Crataegus
studies)                level                   extract
                        (c)

                                           N   Diff (a)

MWL(W)                  All              188      +7.94

(Hanak and Bruckel      Low                U     +24.20

(1983),                 Moder.            94    + 11.66
Zapfe et al. (2001),    low

and Tauchert(2002))     Moder.            62      +2.48
                        high

                        High              21      -1.16

LVEF (%) during         All               78      +2.43

exercise (Eichstadt     Low               16      +2.14

et al. (1989),          Moder.            29      +2.97
Eichstadt et al.        low

2001, and Eichstadt     Moder.            20      +1.58
etal.(2003))            high

                        High              13      +2.32

PRHPI (mmHg/min) after  All              163      -9.03

2 min 50 W vs. resting  Low               41      +3.16

(O'Conolly et al.       Moder.            55      -7.40
(1986,1987),            low

Leuchtgens (1993),      Moder.            38     -11.74
Weikl et al. (1996),    high

Zapfe et al. (2001),    High              29     -25.79
and Eichstadt
et al.(2003))

Parameter (pooled       Placebo          P (b)
studies)

                              N   Diff
                                   (a)

MWL(W)                      118  +1.34   0.013

(Hanak and Bruckel            7      +

(1983),                          14.57

Zapfe et al. (2001),         45  +8.70

and Tauchert(2002))          39  -2.68

                             27  -8.54

LVEF (%) during              60  +0.43  <0.001

exercise (Eichstadt              +0.94

et al. (1989),               16  +0.29

Eichstadt et al. 2001,       22  +0.55

and Eichstadt etal.          13  +0.05
(2003))

PRHPI (mmHg/min) after      164  +3.73  <0.001

2 min 50 W vs. resting       47  +7.88

(O'Conolly et al.                +2.23

(1986,1987),                     -1.71

Leuchtgens (1993),           27  +6.31

Weikl et al. (1996),
Zapfe et al. (2001),
and Eichstadt et
al.(2003))

(a)Mean changes from baseline.
(b )Wilcoxon test, 2-sided.
(c) Subgroups separators from low to high baseline values:
MWL: [Less than or equal to] 25 W, > 25 and [Less than or equal to]
50W. > 50 and [Less than or equal to] 75 W, > 75 W.
LVEF: [Less than or equal to] 40%. > 40 and [Less than or equal to]
45%, > 45 and [Less than or equal to] 50%, > 50%. PHRPI:
[Less than or equal to] 45 mmHg/min, > 45 and [Less than or equal to]
90 mmHg/min, > 90 and [Less than or equal to] 135 mmHg/min, >
135 mmHg/min.


This result is in accordance with data from 202 patients from the cohort study taking Crataegus extract WS[R] 1442. Over a 3-year period, changes in mean MWL were +8.8 W, +12.2 W in the subgroup performing lowest at baseline, +10.1 W in the medium group, and -3.6 W in the best performing group. Linear regression analysis demonstrated a weak relationship ([R.sup.2] = 0.11, p < 0.001) between initial values and treatment effect in the total population as well as in men and in women separately. Female patients started from a lower mean level and their gain in MWL was larger (Fig. 1).

LVEF increased in active treatment (+1.8) and placebo (+0.5) groups at rest (3 studies, N=140, p = 0.002) and during steady state exercise (3 studies, N= 138). With exercise, improvement was six times higher under active treatment in the pooled population (p < 0.001). The increase did not vary systematically by baseline levels (Fig. 2). Comparable results were obtained when the analysis was restricted to the two placebo-controlled trials (data not shown).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

PHRPI at 50 W workload had lowered by the end of treatment under active treatment (-9.03 mmHg/min, corresponding to -11% of the initial value) but not under placebo (+3.73 mmHg/min, 6 trials, N = 327, p < 0.001). The treatment effect of Crataegus extract increased with higher baseline values while there was no clear trend with placebo (Table 3).

Analysis of data from 155 patients taking WS[R] 1442 in the cohort study also revealed a reduction of PHRP at 50 W after 3 years by 10%, -12% in men and -9% in women. Effect size was correlated with baseline values in men as well as in women ([R.sup.2]-0.55 and 0.26; p < 0.001).

Effects on symptoms

The total score of items in the von Zerssen list decreased from 23.45 to 12.65 in the active treatment group and from 22.10 to 16.64 in the placebo group (3 studies, N=278, p < 0.001). Comparable reductions were observed in men (-10.81 WS[R] 1442 vs. -6.21 placebo) and women (-10.80 vs. -5.33). Subgroup analysis of patients with baseline levels either below or above median (21 points) revealed, that absolute improvement is larger in those patients with more complaints at baseline than in those with less baseline symptoms due to a floor effect (Fig. 3): the low starting value of 9.53 points and the 25% percentile of 4 points in this group indicate that there were many patients which simply could not improve on this scale. Relative improvements in patients with baseline levels either below or above median were -27% versus -51% for WS[R] 1442. -9% versus -30% for placebo.

Improvement was greater with active treatment (p < 0.01) for the following items: lump in the throat, dyspnea, weakness, fatigue, nausea, irritability, worrying, lumbago or back pain, restlessness, and tremble.

Data from the cohort study corroborated these findings: Total score of MLHF-score improved from 27.2 points to 15.5 points (N= 366, p<0.001), with women (N = 258, 27.5 to 15.4, p < 0.001) having somewhat greater improvements from higher baseline than men (N=108, 25.9 to 15.9, p < 0.001). Most of the improvement was accomplished within the first 6 months, when total score had decreased to 18 points (Fig. 4).

Fig. 5 shows the results for the specific symptoms, with items arranged in the order of decreasing baseline severity. The most frequent, physical items were improved by about 40-50%.

[FIGURE 4 OMITTED]

Association of symptomatic and objective improvement

Change in total von Zerssen symptom score correlated weakly with change in MWL, both in the active treatment group ([R.sup.2] = 0.04, p = 0.018) and in the placebo group ([R.sup.2] = 0.10, p = 0.007).

Improvement of typical symptoms was associated with improvement of MWL for each of the 4 typical symptoms (p < 0.001) in the WS[R] 1442 group, but not in the placebo group (Fig. 6),

These results are in accordance with findings from cohort study. More patients with increase in MWL showed improvement in typical symptoms than patients without MWL-improvement. Furthermore, there was a correlation between improvement in exertional dyspnoe and decrease in PHRP at 50 W (N= 252, p = 0.009).

Discussion

The 3 physiologic outcome parameters investigated in the present analysis display different patterns in their relation of treatment effect to baseline conditions. LVEF improved independently from baseline. PHRPI did not improve under placebo, while active treatment was effective in all categories but dramatically more in patients with highest baseline values, i.e. with poorest starting conditions. MWL improved more in both treatment groups when baseline levels were low. These results are compatible with known pharmacological effects of Crataegus extracts such as WS[R] 1442: Positive inotropy by inhibition of myocardial [Na.sup.+]/[K.sup.+]-ATPase (Schwinger et al. 2000) would be expected to improve LVEF throughout the range represented in our study population. Amplification of endothelial-dependent vasodilation by augmentation of endothelial NO- and EDHF-release (Anselm et al. 2009; Brixius et al. 2006) will reduce vascular resistance during exercise most in those patients with most impaired endothelial function and will be less effective in patients with preserved vasoreactivity. Thus, patients with high PRPI and low MWL would be expected to benefit most.

Symptoms and complaints of various complexity and more or less closely related to heart failure were recorded in the studies. Strong and significant improvements were found especially in typical physical symptoms of heart failure like dyspnea, weakness or fatigue, and also in some psychological symptoms like worrying, irritability or restlessness. Improvement in core symptoms was moderately associated with physiologic outcome parameters. It is reasonable to suppose that pharmacologic effects of Crataegus extract improve physiologic parameters leading causally to symptom reduction, an increase in well-being and mental state.

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Both sexes could benefit from treatment with Crataegus extract; quantitative differences in improvement were usually associated with different baseline levels between sexes and sufficiently explained by correlations between baseline and treatment effect in general.

The present exploratory analysis used pooled data from patients in various stages of heart failure (NYHA I-III) from studies with different treatment durations and dosages. Therefore the results should be interpreted as indicative of some general characteristics of Crataegus treatment effects, they cannot be directly extrapolated to specific treatment situations. A comparable approach was used in a Cochrane meta-analysis by Pittler et al. (2008) who also included some studies performed with other hawthorn extracts than WS[R] 1442. The authors found that Crataegus extract significantly improves physiologic outcomes like maximal workload, left ventricular ejection fraction and pressure-heart rate product, as well as symptoms of heart failure in patients with NYHA I--III-Our results from pooled studies confirm and extend Pittlers findings, based on individual patient data. Results from the 3-year cohort study were in all aspects in line with results from our pooled analyses. This consistency of observations supports the notion that we were able to describe some general aspects of Crataegus treatment characteristics.

However, it should be noted that median baseline LVEF at rest was 43% with a lower quartile of 38% in our analysis, thus representing mainly patients with low normal to mildly impaired left ventricular systolic function. A moderate improvement in LVEF was reported by Zick et al. (2009) in patients with more advanced heart failure (NYHA II--III and mean LVEF of 36% despite optimal baseline treatment). Data from the SPICE trial (Holubarsch et al. 2008) were not included into this pooled analysis, as SPICE was conducted in patients with NYHA class II or III CHF and reduced left ventricular ejection fraction (mean LVEF 24%) despite optimal standard treatment. Such patients suffer from far more advanced ventricular dysfunction than those in the studies analysed, and are not representative of patients typically receiving Crataegus extract treatment (Eggeling et al. 2006).

In conclusion, Crataegus extract treatment effects on physiologic outcomes and typical symptoms are modulated by baseline severity. The strongest effects were described in patients with more impaired baseline conditions. In patients with mild symptoms, effect sizes were small due to floor effects of the measures employed. Taking baseline differences into account, benefits were comparable in male and female patients with impaired exercise-tolerance in early chronic heart-failure.

Conflict of interest

Thomas Eggeling has received fees for speaking on conference from the manufacturer (Schwabe). Vera Regitz-Zagrosek has received a grant for research on Crataegus and has received fees for speaking on conference from the manufacturer (Schwabe).

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Thomas Eggeling (a), Vera Regitz-Zagrosek (b), *, Andrea Zimmermann (c), Martin Burkart (c)

(a) Kardiologie Koln, Gemeinschaftspraxis Kardiologie, Josef-Haubrich-Hof5, 50676 Koln, Germany

(b) Berlin Institute of Gender in Medicine (GiM), Center for Cardiovascular Research (CCR), Charite Campus Mitte, Hessische Str. 3-4, 10115 Berlin, Germany

(c) Dr. Willmar Schwabe GmbH & Co. KG, Willmar-Schwabe-Strafie 4, 76227 Karlsruhe, Germany

* Corresponding author. Tel.: +49 30 450 525 172; fax: +49 30 450 7 525 288.

E-mail address: vera.regitz-zagrosek@charite.de (V. Regitz-Zagrosek).

doi:10.1016/j.phymed.2011.06.022
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Author:Eggeling, Thomas; Regitz-Zagrosek, Vera; Zimmermann, Andrea; Burkart, Martin
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:Nov 15, 2011
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