Benefit-Risk Assessment of Crataegus Extract WS 1442

An Evidence-Based Review

Christian J. F. Holubarsch; Wilson S. Colucci; Jaan Eha


Am J Cardiovasc Drugs. 2018;18(1):25-36. 

In This Article

Clinical Efficacy

Treatment of heart failure is aimed at reducing morbidity and hospitalization as well as at improving heart failure emergent symptoms and health related quality of life (QoL). While trials investigating the efficacy of treatment in heart failure have previously focused mainly on mortality, current heart failure disease management guidelines increasingly recognize the importance of improving symptoms and QoL as patient-relevant outcomes. An example of this shift is a change in the description of the objectives of heart failure treatment between the European Society of Cardiology "Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure" of 2008 and 2012: whereas in the 2008 document it is stated that "The purpose of diagnosing and treating heart failure is no different from any other medical condition, namely to bring about a reduction of mortality and morbidity"[48] (p. 2404), the authors of the 2012 revision recognize that "The goals of treatment in patients with established heart failure are to relieve symptoms and signs …, prevent hospital admission, and improve survival"[49] (p. 1804). In addition to improving survival and reducing hospitalization, the relief of symptoms such as dyspnea, fatigue, tiredness, or edema, as well as improvement in QoL and an increase in functional capacity, are thus also of the utmost importance to patients.[50] Moreover, a lack of improvement in health-related QoL after hospital discharge has been identified as a powerful predictor of re-hospitalization and mortality.[51]


The effect of WS 1442 on mortality and hospitalization in NYHA class II–III HFrEF was investigated in the SPICE study, a 24-month, randomized, placebo-controlled trial.[39,40] The primary endpoint was the time until the first cardiac event, defined as a composite endpoint of death of cardiac cause, non-fatal myocardial infarction, or hospitalization due to progressive heart failure. During 2 years of treatment, cumulative first cardiac event rates were lower with WS 1442 compared to placebo, albeit without reaching statistical significance (Figure 1). Moreover, participants treated with WS 1442 were at a lower cumulative risk of cardiac mortality and sudden cardiac death (Figure 2), notably in patients with baseline LVEF between 25 and 35% (upper limit for inclusion). In this subset, the difference with respect to placebo was descriptively significant at months 12, 18, and 24 in favor of WS 1442 for sudden cardiac death (Figure 3). The results point to a potential antiarrhythmic and/or anti-ischemic effect already observed in animal models, where WS 1442 prevented reperfusion arrhythmias effectively. This is particularly important considering adverse reactions to chemical antiarrhythmics including amiodarone, since the reduction of the risk of sudden cardiac death was accomplished by WS 1442 without observing adverse reactions.

Figure 1.

Cumulative hazard for time to first cardiac event (from 40)

Figure 2.

Cumulative hazard for cardiac mortality (a, c) and sudden cardiac death (b, d): all patients (a, b) or patients with LVEF ≥ 25% (c, d) (from [40]). LVEF left ventricular ejection fraction

Figure 3.

Cardiac mortality and sudden cardiac death in total population and subgroup LVEF ≥ 25% (hazard ratios, 95% confidence intervals and two-sided log-rank test p values) (from [40]). LVEF left ventricular ejection fraction

Quality of Life and Exercise Tolerance

The effect of WS 1442 on symptoms of heart failure and QoL-related outcomes was investigated in several smaller trials, most of which were included in a Cochrane review of hawthorn extracts for treating chronic heart failure.[52] The authors identified 28 and included 14 trials which were performed in patients using a hawthorn monopreparation and which were randomized and placebo controlled. Of the 14 eligible trials, 11 used WS 1442, while three used LI 132, a methanolic extract standardized to a content of 2.2% flavonoids. For WS 1442, the effect on symptoms and/or health-related QoL was also investigated in controlled studies completed only after finalization of the Cochrane review.[40,43,45]

Exercise tolerance tests were performed in four trials included in the Cochrane review.[37,53,54,55] A meta-analysis of maximum workload (Figure 4), in which the WS 1442 900 and 1800 mg/day groups investigated by Tauchert[37] were analyzed separately, showed a statistically significant increase over placebo by a weighted mean difference of 5.4 W [95% confidence interval (CI) 0.7–10.0, p = 0.024]. Moreover, based on a meta-analysis of two trials,[54,55] the exercise tolerance was increased significantly by a weighted mean difference of 122.8 W min (95% CI 32.7–212.8, p < 0.01).

Figure 4.

Maximum workload (W): meta-analysis of difference between Crataegus and placebo for change from baseline (means and 95% confidence intervals, random effects model)

Data from,[52] Figure 1.1, based on studies reported by Bödigheimer and Chase[53] (LI 132), Hanak and Brückel,[54] Tauchert[37] and Zapfe[55] (all WS 1442)

The pressure-heart rate product, an index of cardiac oxygen consumption, was assessed in five trials included in the Cochrane review[55–59] and performed with WS 1442. Compared to placebo, meta-analysis showed a significant reduction of the pressure-heart rate product in WS 1442-treated patients by a weighted mean difference of 19.2 mmHg/min (95% CI 8.0–30.5, p < 0.01) as well as significant reductions in four of the five primary trials.[52] The results indicate a significant increase in cardiac performance in patients treated with WS 1442.

In patients with HFrEF, Eichstädt et al.[60] as well as Zick et al.[43] observed improvements of reduced LVEF, with moderate but statistically significant advantages for WS 1442 over placebo (p < 0.01 and p = 0.04, respectively).

In the trial performed by Härtel et al.[45] in 140 patients with HFpEF, in which 8 weeks of exercise training (bi-weekly, 90-min, supervised training sessions and aerobic walking) alone (70 patients) was compared to exercise training plus 900 mg WS 1442 per day, physical exercise capacity was analyzed by a 2-km walking test performed at baseline and treatment end (70 patients). Whereas patients randomized to WS 1442 showed a reduction of the time needed to accomplish the 2-km distance from an average of 23.0 to 20.1 min (reduction of 12.7% of the baseline value), the patients in the control group showed a reduction from 21.4 to 19.6 min (−8.4%). The difference was statistically significant (p = 0.02; Figure 5). In patients with HFrEF, Zick et al.[43] found an increase in 6-min walking distance from an average of 358 to 371 m for WS 1442 and from 374 to 379 m for placebo, but the difference was not significant at the 5% level.

Figure 5.

Time for 2-km walking test (means and standard deviations; data from [45])

Changes in heart failure-associated symptoms and health-related QoL during treatment with WS 1442 were assessed in several trials.[37,43,45,56,57] In two trials, the von Zerssen Complaints List,[61] a validated self-rating questionnaire assessing 24 general symptoms, some of which (e.g., shortness of breath, fatigue) are particularly important in heart failure, was used. In the study reported by Leuchtgens,[56] which included 30 patients (15 per group), those treated with WS 1442 for 8 weeks showed a significantly more pronounced decrease of the total score of the scale than those in the placebo group (mean value difference 7.3 points, 95% CI 0.9–13.7, according to[52]). In the study of Tauchert[37] in which 209 patients received 1800 or 900 mg/day WS 1442 or placebo for 16 weeks, both WS 1442 dosages showed a significantly more pronounced total score decrease compared to placebo (Figure 6).

Figure 6.

Reduction in the total score of von Zerssen Complaints (means, standard deviations, and two-sided p values; from [37], Figure 4, and [81])

Tauchert[37] also used an ad hoc score assessing the four "typical" heart failure symptoms, i.e., general capability, lassitude, early fatigability, and effort dyspnea. At the end of the 16-week treatment phase, the treatment group differences to placebo for score change versus baseline were significant for WS 1442 900 mg/day (p = 0.04) and 1800 mg/day (p = 0.004).

Weikl et al.[57] used a health-related QoL inventory developed by Siegrist and Junge[62] for chronically ill patients and including items focusing on functional capacity (symptom burden, ability to enjoy and relax, positive and negative mood, sociableness, and allegiance). The authors report on a trend towards more pronounced improvement of all symptoms assessed in patients treated with WS 1442 as compared to placebo. During the baseline examination, the 136 patients included in the trial were also asked to identify and rate their main symptoms and complaints associated with heart failure. After 8 weeks of treatment, improvement of these symptoms was observed in 59% of 63 patients exposed to WS 1442 and in 44% of 68 patients treated with placebo.

The EuroQol-5D questionnaire[63] was used in the study of Zick et al.[43] for assessing health-related QoL after 6 months' treatment with WS 1442 or placebo in 120 patients. No significant differences were found.

In an open-label, exploratory study, Härtel et al.[45] used the Kansas City Cardiomyopathy Questionnaire (KCCQ),[64] specifically developed for assessing QoL in patients with chronic heart failure, to investigate 140 patients with HFpEF undergoing 8 weeks' endurance exercise training with or without co-administration of WS 1442. The study was neither intended nor powered for demonstrating superiority of WS 1442 co-administration, and, moreover, the authors observed a ceiling effect in some of the KCCQ subscales already in patients undergoing exercise training alone so that further improvement in WS 1442-treated patients could hardly be expected. Nevertheless, in the Symptoms scale of the KCCQ, assessing the frequency and bothersomeness of edema, fatigue, and dyspnea as well as having to sleep in a sitting position or to use a supporting pillow to ameliorate shortness of breath, the summary score improved by 10 ± 17 points (mean ± standard deviation) in the WS 1442 group compared to 5 ± 14 points in the control group. Moreover, each of the symptoms assessed showed a more favorable outcome in patients with co-administered WS 1442 (Figure 7). The validity of the QoL results is limited by potential bias attributable to the open-label design of the study and may deserve confirmation in an adequately powered, double-blind, placebo-controlled trial. The incidence rate of AEs in patients receiving WS 1442 was lower than in those using exercise training alone (13 vs. 17%).

Figure 7.

Average change in frequency and intensity of heart failure symptoms assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) (from [45], Figure 4)