Review of Proprietary Hawthorn Extract WS® 1442 for Treating Heart Failure

The leaves and flowers of hawthorn (Crataegus laevigata and C. monogyna, Rosaceae) have been used to treat heart ailments for over 2000 years. Based on the cumulative scientific evidence, the German Commission E issued positive monographs for Hawthorn to treat decreasing functional capacity of the heart, and in 2016, the European Medicines Agency’s Committee on Herbal Medicinal Products recognized hawthorn as a “traditional herbal medicinal product used to relieve symptoms of temporary nervous cardiac complaints … .”1

One of the most extensively studied hawthorn preparations is the proprietary extract WS® 1442 (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany). This review and risk-benefit analysis focuses on the safety and efficacy of WS 1442 in the treatment of patients with New York Heart Association (NYHA) class II or class III heart failure, including sub-analyses of the effects of WS 1442 on patients with systolic heart failure (heart failure with reduced ejection fraction [HFrEF]) and diastolic heart failure (heart failure with preserved ejection fraction [HFpEF]).

WS 1442 is a 4-6.6:1 dry extract of hawthorn flowers with leaves (extraction solvent 45% ethanol) containing 17.3-20.1% oligomeric procyanidins, as well as flavonoids, triterpenoids, and phenol carboxylic acids. An overview of 24 preclinical studies of WS 1442 is provided, the results of which may be summarized as follows: positive inotropic and antiarrhythmic properties; myocardial protection from ischemic damage, reperfusion injury, and hypertension-related hypertrophy; improved endothelial functions such as nitric oxide synthesis; and delayed endothelial senescence.

WS 1442 Safety

A 2006 systematic review of hawthorn safety identified 14 studies of WS 1442, including 10 randomized controlled trials (RCTs), two uncontrolled trials, one observational study, and one cohort study. A cumulative total of 1563 subjects (395 enrolled in RCTs and 1168 in uncontrolled trials) consumed WS 1442 at doses up to 1800 mg/day for up to 16 weeks. One trial included healthy subjects while the remainder recruited patients with NYHA class I-III heart failure. In the RCTs, the incidence of adverse effects (AEs) did not significantly differ between the WS 1442 and control groups. No causal relationship was seen between WS 1442 dose and AEs, and no AE potentially related to WS 1442 was serious.

In the 2008 placebo-controlled, double-blind, multicenter trial SPICE (Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in congestive heart failure), 2681 adults with NYHA class II or III congestive heart failure and reduced left ventricular ejection fraction (LVEF) received 900 mg daily of WS 1442 or placebo for 24 months as an adjunct to guideline cardiac medications. About 90% of the participants took at least three cardioactive drugs. The incidence of serious AEs was 39.2% in the WS 1442 group and 41.1% in the placebo group, with similar types of AEs reported in both groups and no specific AEs related to WS 1442 observed.

In the 2009 Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) trial (n = 120), WS 1442 or placebo was given to patients with NYHA class II-III chronic heart failure to investigate the effect of WS 1442 on submaximal exercise capacity. AEs were experienced by 60% of patients in the WS 1442 group and by 38.3% in the placebo group. Twelve patients in each group reported cardiac-related AEs. The incidence of cardiac AEs and common AEs was comparable between groups. The investigators concluded that it was unlikely that the wide variety of AEs in the hawthorn group may be “explainable by a pharmacological effect of WS 1442 and may have been attributable to chance.”

No suspected AEs or drug interactions attributed to hawthorn have been reported to health authorities. No possible drug interactions with WS 1442 were seen in the hawthorn safety review or the subsequent studies. A crossover study with healthy volunteers found that WS 1442 had no significant effect on digoxin pharmacokinetics.

WS 1442 Efficacy

Heart failure treatments aim to reduce morbidity and hospitalization and improve symptoms and quality of life (QoL). In the SPICE trial (n = 2681), the cumulative first cardiac event rates were lower in the WS 1442 group compared with the placebo group, although the difference between groups was not statistically significant. However, WS 1442 patients with baseline LVEF values at the upper limit for inclusion in the study (25-35%) had a significantly lower cumulative risk of cardiac mortality and sudden cardiac death. “The results point to a potential antiarrhythmic and/or anti-ischemic effect already observed in animal models … .,” write the authors.

The 2008 Cochrane review of hawthorn included 11 RCTs which evaluated the effect of WS 1442 on heart failure symptoms, and QoL meta-analysis of the two WS 1442 trials that evaluated exercise tolerance indicated that exercise tolerance was significantly increased in the WS 1442 group (P < 0.001). The pressure-heart rate product, an index of cardiac oxygen consumption, was assessed in five of the included WS 1442 trials, and meta-analysis of the results showed that the pressure-heart rate product was significantly reduced in WS 1442 patients compared to placebo (P = 0.01), indicating a significant increase in cardiac performance in patients treated with WS 1442.

Two studies in patients with HFrEF found that WS 1442 significantly reduced LVEF compared to placebo (P < 0.01 and P = 0.04, respectively). In the two studies that evaluated the time to accomplish a specified walking distance, one found that WS 1442 significantly reduced the time in patients with HFpEF (P = 0.02), while another found that in patients with HFrEF, WS 1442 had no significant effect. Three studies evaluated the effect of WS 1442 treatment on QoL—one found no significant difference between WS 1442 and placebo; one reported a trend towards significance with WS 1442, and one found WS 1442 significantly improved QoL in patients with HFpEF.

Risk-benefit Assessment

Based on the extant clinical evidence, hawthorn preparations cause few, mainly transient, and non-serious AEs. For WS 1442 in particular, there have been no serious AEs and no indications of possible drug interactions in large-scale, long-term studies. “It is therefore concluded that Crataegus extract WS 1442 has a very favorable safety profile even when administered as a part of a polydrug regimen.” In terms of efficacy, evidence from RCTs indicates that WS 1442 improves cardiac performance and exercise tolerance, ameliorates heart failure symptoms, and improves health-related QoL. The authors conclude that the risk-benefit assessment for WS 1442 in the treatment of patients with NYHA class II or III heart failure is positive.

The authors conclude that WS 1442 is a safe herbal medicine product that improves functional capacity, symptom control, and health-related QoL in patients with HFrEF and HFpEF. They acknowledge that a limitation of this review “is that some of the evidence presented in our review originated from older, comparatively small, and partly uncontrolled research so confirmation by controlled trials meeting current rigorous scientific standards would be highly welcome.”

All of the authors received honoraria from Dr. Willmar Schwabe GmbH & Co. KG for conducting and writing for the SPICE study.

Reference

1European Medicines Agency Committee on Herbal Medicinal Products (HMPC). European Union herbal monograph on Crataegus spp., folium cum flore. London, UK: European Medicines Agency; 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/2016/06/WC500209002.pdf. Accessed March 20, 2018. 

Holubarsch CJF, Colucci WS, Eha J. Benefit-risk assessment of Crataegus extract WS 1442: an evidence-based review. Am J Cardiovasc Drugs. 2018;18(1):25-36.

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