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

Benefit-risk Assessment and Conclusions

Although congestive heart failure may affect people of all ages, most of the burden is borne by individuals aged ≥ 65 years, who account for more than 80% of the deaths and cases of the disease existing in the USA and Europe.[65] In this elderly, often multimorbid population, the resulting polypharmacy is associated with an exponential increase of the risk of adverse effects[66,67] that may ultimately lead to increased mortality.[68,69] The use of drugs that have a favorable safety profile and a low potential for drug interactions is therefore crucial.[70]

There is uniform agreement among researchers that Crataegus preparations cause few and mainly transient, non-serious adverse effects (e.g.,[36,45,46,52]). For WS 1442, no serious adverse reactions have been observed at all to date. In clinical trials, including a large-scale, long-term mortality study with patients receiving polydrug treatment for heart failure (e.g., ACE inhibitors, β-receptor blockers, spironolactone, digitalis, and nitrates in patients with LVEF < 35%), no safety signals and no indications of possible drug interactions were observed,[40] and an interaction with digoxin, which is widely used in HFrEF, has been excluded, thus allowing its safe co-administration.[47] 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 SPICE study did not demonstrate an additional beneficial effect of co-administered WS 1442 on mortality in addition to an existing anti-heart failure treatment regimen individually prescribed in accordance with applicable guidelines, but there is encouraging evidence that WS 1442 may reduce the risk of cardiac mortality and sudden cardiac death at least in a subgroup of patients (Figure 2, Figure 3).[40]

Randomized, controlled studies demonstrate that WS 1442 improves cardiac performance and exercise tolerance in patients with mild to moderately severe heart failure. Moreover, the herbal medicinal product has an ameliorating effect on heart failure emergent symptoms such as edema, dyspnea, and fatigue, and thus alleviates the disease burden of the patients and leads to an improvement of health-related QoL. Importantly, unlike for some other drugs which were also shown to improve such outcomes (e.g.,[71]), no signals were observed that may adversely affect survival.

HFrEF is commonly defined as heart failure with LVEF ≤ 40%, and HFpEF implies LVEF ≥ 50%, whereas patients with LVEF between 41 and 49% may be regarded as suffering from borderline HFpEF (e.g.,[51]). It should be noted that patients of both types of heart failure suffer from similar clinical symptoms. Among the studies considered in this review, the patients of the SPICE study,[40] the HERB CHF study,[43] and the study reported by Eichstädt et al.[60] suffered from HFrEF, whereas those of the study published by Härtel et al.[45] suffered from HFpEF. The protocols of the remaining trials reviewed for efficacy of WS 1442 did not include eligibility criteria for LVEF, but three trials required heart failure according to NYHA class II,[55–57] whereas one required NYHA class III.[37] Although there is no clear association between the NYHA functional classification and LVEF,[49] patients with class II heart failure have been found to mainly exhibit LVEF > 40% (e.g.,[72]), and thus the majority of patients in these trials may likely have suffered from HFpEF.

We agree with the authors of the Cochrane review who concluded that "there is a significant benefit in symptom control and physiologic outcomes from hawthorn extract as an adjunctive treatment for chronic heart failure"[52] (p. 2). In HFrEF, WS 1442 has been shown to improve functional capacity and heart failure-associated symptoms without causing any safety issues despite long-term polypharmacy in a particularly vulnerable patient population. The improvement of functional capacity and symptoms is now recognized as an important objective of heart failure treatment, on one level with the reduction of mortality and hospitalization.[49] The administration of WS 1442 in addition to a guideline polydrug treatment in HFrEF appears to be justified since the anticipated benefit to the patients clearly outweighs the additional risk. In this context, it should be noted that the mortality studies confirming the efficacy of β-blockers, ACE inhibitors and mineralocorticoid receptor antagonists were all performed in patients with LVEF ≤ 35 or ≤ 40% so that a beneficial effect in patients with LVEF > 40% is unproven.[51] Since HFpEF is commonly understood to require LVEF ≥ 50%, WS 1442 may help to close the therapeutic gap between HFrEF and HFpEF, but more studies are needed to corroborate this benefit

A favorable effect on mortality in HFpEF has not been demonstrated for any drug to date. Instead of proposing a gold standard treatment, current guidelines[49,51] are therefore limited to recommending treatments targeting symptom amelioration. In this context, it is important to note that established standard drugs in heart failure treatment, including digitalis, angiotensin II receptor blockers (including irbesartan and candesartan),[73] angiotensin-converting enzyme inhibitors,[74] ivabradine,[75] ranolazine,[76] and spironolactone, failed to improve the clinical outcome or had only moderate beneficial effects in HFpEF.[77–80] WS 1442, on the other hand, has been demonstrated to improve functional capacity, disabling symptoms, and health-related QoL and has a positive inotropic effect without causing specific adverse effects. In the absence of a gold standard therapy in HFpEF, WS 1442 may therefore be an important therapeutic option in addition to the current clinical standards.

We consider it a strength of our review that it provides a comprehensive overview of the available pre-clinical and clinical data for WS 1442 and thus enables a well-founded assessment of its benefits and risks in the treatment of heart failure. A limitation 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.

In conclusion, according to scientific evidence from randomized, controlled clinical trials and post-marketing surveillance data, Crataegus extract WS 1442 is a safe herbal medicinal product with proven, patient-relevant benefits regarding functional capacity, symptom control and health-related QoL in HFrEF and HFpEF. The observed clinical effects of the product can be explained by pre-clinical findings regarding its mode of action. WS 1442 has therefore been shown to have a positive benefit-risk profile for the treatment of both HFrEF and HFpEF as add-on therapy to current clinical practices.

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