Benefit-Risk Assessment of Crataegus Extract WS 1442

An Evidence-Based Review

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

Disclosures

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

In This Article

Abstract and Introduction

Abstract

Preparations from Crataegus (hawthorn) have a long history in the treatment of heart failure. WS 1442 is a dry extract from hawthorn leaves with flowers (4–6.6:1), extraction solvent of ethanol 45% (w/w), adjusted to 17.3–20.1% of oligomeric procyanidins. Nonclinical studies show that WS 1442 has positive inotropic and antiarrhythmic properties and protects the myocardium from ischemic damage, reperfusion injury, and hypertension-related hypertrophy, improves endothelial functions such as NO synthesis, and delays endothelial senescence. Randomized, controlled trials in patients with heart failure have demonstrated that the herbal medicinal product increases functional capacity, alleviates disabling symptoms, and improves health-related quality of life, all of which have become important targets of heart failure therapy according to current disease management guidelines. Clinical trials (including a 2-year mortality study with polypharmacy and > 1300 patients exposed) and post-marketing surveillance studies have shown that WS 1442 has a very favorable safety profile both as monotherapy and as add-on therapy, where no drug interactions have been observed. No specific adverse reactions to WS 1442 are known to date. WS 1442 may thus help to close the therapeutic gap between systolic and diastolic heart failure for which evidence of efficacy for other cardioactive drugs is sparse. Scientific evidence shows that WS 1442 is safe and has a beneficial effect in patients with heart failure corresponding to New York Heart Association classes II or III. The benefit-risk assessment for WS 1442 is therefore positive.

Introduction

The phrase "first do no harm" has been ascribed to Hippocrates (about 460–370 B.C.), but was actually coined by the British physician Thomas Inman as recently as 1860.[1,2] The intention behind the dictum is to remind physicians that they ought to always act in the best interest of their patients. Most medical treatments are inevitably associated with certain risks to the patient; these consequences may be more or less serious and more or less likely to occur depending on the patient and his/her circumstances. Physicians and patients may nevertheless be inclined to accept certain treatment emergent risks if they are outweighed by the expected therapeutic benefit. It is therefore important to assess the over-all risk-benefit ratio of any medical treatment.

Preparations from leaves and flowers of certain species of Crataegus (hawthorn) have been mentioned as remedies in the medical literature since the 1st century A.D.,[3] mainly for treating cardiac diseases and for strengthening the aging heart. In 1896, 43 cases of patients suffering from various forms of heart disease and treated with Crataegus oxyacantha were reported, with promising results.[4] But it was not until the 1930s that systematic scientific research into the clinical effects of Crataegus preparations started, and extracts from Crataegus were introduced into the German pharmacopoeia in 1941. In 1984 and 1994, the German Commission E issued positive monographs for Crataegus leaves with flowers[5] for the treatment of decreasing functional capacity of the heart corresponding to class II of the New York Heart Association (NYHA) Functional Classification, which is characterized by mild cardiac symptoms such as fatigue, palpitation, dyspnea, or anginal pain during ordinary activity.[6] As medicinal products containing Crataegus leaves and flowers have been in use for at least 30 years (15 years within the EU), in 2016, the European Medical Association (EMA), through the Committee on Herbal Medicinal Products (HMPC), recognized the traditional use of Crataegus for the relief of symptoms of temporary nervous cardiac complaints (after serious medical conditions have been excluded).[7] Regarding the safety profile of this product, the EMA concluded that the use of Crataegus leaves and flowers can be regarded as safe when used under the approved indications.[8]

WS 14421 is a dry extract from hawthorn leaves with flowers (4–6.6:1), extraction solvent of ethanol 45% (w/w). The extract is adjusted to 17.3–20.1% oligomeric procyanidins (OPCs). In addition to OPCs, the extract contains several flavonoids, including hyperoside, vitexin-rhamnoside, rutin, and vitexin as well as triterpenoids and phenol carboxylic acids. WS 1442 complies with the requirements of the European pharmacopoeia.

The safety and efficacy of Crataegus containing products have been studied and reviewed extensively,[9,10] and WS 1442 is probably the most rigorously studied extract on the market. This work provides a comprehensive overview of the safety and efficacy of WS 1442 in NYHA class II and III heart failure and assesses the risk-benefit ratio of the product, also considering different types of heart failure, i.e., systolic heart failure [heart failure with reduced ejection fraction (HFrEF)] and diastolic heart failure [heart failure with preserved ejection fraction (HFpEF)].

1WS® 1442 is the active substance of Crataegutt® (Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany).

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