Reviewed: 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.

The leaves and flowers of hawthorn (Crataegus laevigata and C. monogyna, Rosaceae) have been used to treat heart ailments for more than 2,000 years. Based on the cumulative scientific evidence, the German Commission E issued positive monographs for hawthorn berry and leaf with flower preparations to treat decreasing functional capacity of the heart,¹ 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.”²

One of the most extensively studied hawthorn preparations is the proprietary extract WS 1442 (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany). WS 1442 is a dry extract of hawthorn flowers and leaves (drug extract ratio of 4-6.6:1; extraction solvent 45% ethanol) containing 17.3% to 20.1% oligomeric procyanidins, as well as flavonoids, triterpenoids, and phenol carboxylic acids.

This review and risk-benefit analysis focused 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, and included 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]).

An overview of 24 preclinical studies of WS 1442 is provided. The results of the studies support WS 1442’s ability to provide positive inotropic properties (strengthening the force of heart contractions) and antiarrhythmic properties; myocardial protection from ischemic damage (damage caused by restricted blood supply to tissue), reperfusion injury (injury caused by return of blood supply to tissue), and hypertension-related hypertrophy; improved endothelial functions such as nitric oxide synthesis; and delayed endothelial senescence (age-related deterioration of the endothelium).

Safety Review

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 1,563 subjects (n = 395 in controlled trials and n = 1,168 in uncontrolled studies) consumed WS 1442 at doses up to 1,800 mg per day for up to 16 weeks. One trial included healthy subjects, while the remainder recruited patients with NYHA class I-II or II-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 found between WS 1442 dose and AEs, and no AE potentially related to WS 1442 was considered serious.

In the 2008 placebo-controlled, double-blind, multicenter SPICE (Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in Congestive Heart Failure) trial, 2,681 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 standard cardiac medications. About 90% of the participants took at least three conventional 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. No specific AEs related to WS 1442 were 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, and no possible drug interactions with WS 1442 were observed in the reviewed trials.

Efficacy Data

Heart failure treatments aim to reduce morbidity and hospitalization and improve symptoms and quality of life (QoL). In the SPICE trial, 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 for cardiac mortality and sudden cardiac death compared to the placebo group. “The results point to a potential antiarrhythmic and/or anti-ischemic effect already observed in animal models,” wrote the authors.

The 2008 Cochrane review of hawthorn included 11 RCTs that 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 from baseline 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 the other found that WS 1442 had no significant effect in patients with HFrEF. 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 toward 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 appear to 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,” the authors wrote. In terms of efficacy, evidence from RCTs indicates that WS 1442 can improve cardiac performance and exercise tolerance, ameliorate heart failure symptoms, and improve cardiovascular health-related QoL. The authors also noted 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 concluded that WS 1442 is a safe herbal medicinal product that can improve functional capacity, symptom control, and cardiovascular health-related QoL in patients with HFrEF and HFpEF. They acknowledged that a limitation of this review “is that some of the evidence ... originated from older, comparatively small, and partly uncontrolled research, so confirmation by controlled trials meeting current rigorous scientific standards would be highly welcome.”

—Shari Henson

References

1. Blumenthal M, Busse WR, Goldberg A, et al., eds. The Complete German Commission E Monographs—Therapeutic Guide to Herbal Medicines. Austin, TX: American Botanical Council; Boston, MA: Integrative Medicine Communication. 1998.
2. European 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: www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Herbal_monograph/2016/06/WC500209002.pdf. Accessed March 20, 2018.