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Ivy Leaf Extracts for the Treatment of Respiratory Tract Diseases Accompanied by Cough: A Systematic Review of Clinical Trials

Summary

Ivy (Hedera helix, Araliaceae) leaf extracts have long been used to treat respiratory diseases, and they are widely accepted by patients and health care providers for this purpose. This systematic literature review evaluates clinical data on the efficacy and safety of ivy leaf extracts in different dosage forms for the therapy of respiratory diseases accompanied by cough. Nineteen clinical studies are evaluated. Among these are eight randomized clinical trials, two non-randomized controlled studies, and nine observational studies. Just one of the 19 reviewed studies was performed in a randomized, placebo-controlled, and double-blind design and fulfilled current criteria for randomized controlled trials (RCTs). The reviewed data indicate that ivy leaf extracts have a secretolytic effect in acute cough, although their efficacy for the treatment of chronic respiratory diseases is inconclusive. Adverse events (AEs) were rare and mostly related to gastrointestinal disorders or allergic reactions. No serious AEs were described.

Background

Ivy is a vine that can climb to 20 meters (66 feet) with evergreen and dimorphic leaves. On non-flowering branches, the leaves have three to five lobes with white, fan-like venation, whereas on flowering branches, they are rhombic or lanceolate.1 The taste and mouthfeel of the dried leaf have been described as bitter and raspy, respectively.2

Ivy leaves contain constituents such as flavonoid glycosides, phenolic acids, polyacetylenes, and saponins.3 In vitro studies indicate that the monodesmosidic (a term that describes a molecule with a single glycoside chain) saponin α-hederin, which can emerge from the bisdesmosidic saponin hederacoside C during the drying process,2 contributes to the overall pharmacological activity of ivy leaf extracts.4-6 The underlying mechanisms are not yet fully understood, but pharmacological data suggest an increase in the β2-adrenergic responsiveness of alveolar type II cells and bronchial muscle cells may lead to the secretolytic and bronchospasmolytic effects observed in clinical studies.7

Clinical data have been obtained with various ivy extracts. Extracts with different drug extract ratios (DERs; see Table 1 for a full list of abbreviations used in this article) and/or different extraction solvents should be considered distinct active ingredients in herbal medicinal products, and results obtained in studies with distinct extracts are generally not interchangeable. Despite the available evidence on the pharmacological activities of α-hederin, neither standardization nor quantification of the α-hederin content in ivy leaf extracts has been performed so far. In addition, other detailed information on the composition of extracts used in clinical studies has not been reported. This also applies to the extracts used in pharmacological studies.

As a result of its anatomy, the respiratory tract in particular is exposed to a multitude of infectious, chemical, and physical sources of irritation. Thus, respiratory tract diseases are common. Acute and chronic forms of cough as a symptom of respiratory tract diseases can be distinguished. The common cold is a viral infection of the upper respiratory tract and the most frequent cause of acute cough. In about two-thirds of cases, this disease is self-limiting within two weeks. Acute bronchitis (AB) is accompanied by dry and, later, productive cough, and often fever, sore throat, and rhinitis.8 Cough is considered to be productive (i.e., wet, with phlegm) if the amount of daily expectoration is at least 30 mL.9

To characterize respiratory diseases, the analysis of lung function via spirometry is a widely used method. Spirometry involves the recording and interpretation of a flow-volume curve and provides information about vital capacity (VC), forced vital capacity (FVC), forced expiratory volume (FEV) in one second (FEV1), and maximal expiratory flow (MEF) of the lungs. The explanatory power of this diagnostic method depends on patient cooperation and the qualification of the examiner.10 Therefore, researchers may choose to use additional analytical techniques. Body plethysmography, for example, can provide information about functional residual capacity (FRC), specific airway resistance (sRAW), lung residual volume (RV), total lung capacity (TLC), intrathoracic gas volume (ITGV), and airway resistance (RAW).11

Although time thresholds can overlap, chronic cough is defined as a cough that persists for longer than eight weeks.8 Asthma is a chronic inflammatory airway obstruction that is reversible (in contrast to chronic obstructive pulmonary disease [COPD], which is considered irreversible) and accompanied by bronchial hyper-reactivity. Differentiating between asthma and COPD is clinically relevant, especially in adults, since symptoms may overlap but treatment options differ. A bronchodilation test is an essential diagnostic tool that describes the reversibility of airway obstructions. To this end, FEV1 is measured before and after inhalation of a short-acting ß-sympathomimetic bronchodilator. Asthma is characterized by a change in FEV1 (∆FEV1) that is greater than 15%, whereas COPD presents as a ∆FEV1 of less than 15%. The course of disease is episodic for asthma and progredient (i.e., progressive) in the case of COPD. Moreover, COPD can be accompanied by pulmonary emphysema. Peak expiratory flow (PEF) can be monitored with a peak flow meter for the evaluation of therapy success and progression control of respiratory diseases, especially in asthma.12,13

Expectorants are a valuable therapeutic option in acute and chronic respiratory diseases. In this context, herbal remedies have a long and well-documented tradition of use. Single-chemical entities, such as ambroxol and acetylcysteine (ACC), are also commonly used expectorants. Several European Union (EU) countries have authorized herbal medicinal products that contain ivy leaf extracts based on their well-established medicinal use as an expectorant in cases of productive cough.14

This review will evaluate the clinical data on the efficacy and safety of ivy leaf extracts for the therapy of respiratory diseases accompanied by cough.

Methods

Systematic Literature Search

The MEDLINE (via PubMed) and Embase (via STN International) databases were searched in October 2016 for primary scientific literature with a focus on clinical data assessing the safety and efficacy of ivy preparations as an expectorant in cases of productive cough. Since the Committee on Herbal Medicinal Products (HMPC) published a final EU herbal monograph 14 and an assessment report 15 on H. helix leaf in 2015, the retrieval period covered the gap between the last assessment of literature cited in the assessment report and the retrieval date (i.e., 2012-2016). To ensure completeness of the retrieval, a systematic approach was chosen that combined keyword searches (in the title and abstract) with the US National Library of Medicine’s Medical Subject Headings, a controlled thesaurus of medical vocabulary. Search terms were as follows: hedera, ivy, Efeu, cough, respiratory tract diseases, respiratory mucosa, signs and symptoms respiratory. These terms were further connected with logical operators according to the PICO Model (a set of guidelines for clinical questions) in order to increase precision of the records found.

Overall, 204 records were retrieved from MEDLINE. The Cochrane Highly Sensitive Search Strategy, which was used to identify randomized clinical trials in MEDLINE, retrieved 13 RCTs from the 204 records. The Embase search was conducted in the basic index mode, which contains single words from the title, abstract, controlled terms, chemical name, and corporate (manufacturer) name, as well as Chemical Abstracts Service Registry Numbers. Different spellings were taken into account by setting the commands accordingly. A total of 66 citations were retrieved from Embase for the period from 2012 to 2016, applying a search strategy similar to the one used in MEDLINE.

Furthermore, several clinical trial registries were screened: ClinicalTrials.gov (a registry of clinical trials in the United States); EU Clinical Trials Register; PharmNet.Bund; and International Clinical Trials Registry Platform. In addition, the following clinical practice guidelines were reviewed: Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (the Association of the Scientific Medical Societies in Germany), Nationale Versorgungsleitlinien, Evidence-Based Medicine Guidelines, and the guidelines developed by the World Health Organization. Overall, 75 records were retrieved from these sources.

All databases were searched irrespective of language and publication status, and no limitations on document types were set. A manual search by checking the reference lists of the retrieved articles and the use of standard textbooks completed the search procedure for relevant documents and information. All references were retrieved in a citation management tool and, after a duplicate check, a total of 369 citations were retrieved.

Literature Screening

All retrieved publications were screened for inclusion criteria. Therefore, titles and abstracts were searched for the use of ivy as an intervention and the indication of respiratory disease in a clinical setting. Studies that did not meet these criteria were excluded. All full texts of the included studies were screened for valuable information corresponding to the addressed question. Here, only German or English full texts could be evaluated. The full texts of two clinical studies were not available16,17 and, therefore, could not be considered in this review. Moreover, reviews and two studies with only historical meaning were excluded.18,19 Ultimately, 19 clinical studies were evaluated in the context of this review.

Data Analysis and Quality Assessment

All reviewed studies were classified according to their study design in terms of evidence levels (Table 2). Controlled studies were further categorized depending on the kind of study control (placebo, active comparator, or other ivy leaf extract formulations). The quality of included studies was assessed using methodological checklists created by the Scottish Intercollegiate Guidelines Network.20 These checklists address questions about the study design, procedure with and number of dropouts, validity of outcome measurements, and statistical power. A summary of study specifics can be found in Table 3.

Results

Placebo-controlled Studies

In 2016, Schaefer et al.21 conducted a randomized, placebo-controlled, double-blind, multicenter clinical study that assessed the efficacy and safety of ivy leaf extract for the treatment of acute cough in adults. The researchers used the cough liquid formulation Prospan Hustenliquid (Engelhard Arzneimittel GmbH & Co. KG; Niederdorfelden, Germany), which is characterized by a DER of 5-7.5:1 using a 30% (m/m) ethanol extraction solvent. A total of 181 patients (18-75 years of age) across five sites were included, and 178 patients completed the trial. Daily drug dose was 105 mg of ivy leaf extract over a treatment period of seven days, whereas the control group received what the authors described as an “inactive, adequate placebo.” The primary outcome variable was cough severity assessed via visual analogue scale (VAS) over the whole treatment period of seven days, at the end of the seven-day treatment period, and at the end of the one-week observation period (day 14). Cough severity was also assessed by the bronchitis severity scale (BSS) and the verbal category descriptive (VCD) scale over the whole treatment period of seven days, as well as a global efficacy assessment (GEA) on days seven and 14.

BSS is a validated instrument to determine the severity of AB in clinical studies. Investigators score the symptoms of AB in the presence of the patient. It contains patient-reported and investigator-assessed items.22 VAS is used as a subjective assessment to quantify cough severity. Therefore, patients are asked to mark their impression on a 100-mm scale from “no cough” to “worst cough severity.” When evaluating acute cough, the minimal important difference (MID) is defined as 17 mm.23 Currently, there are limited data to determine the validity of VAS.24,25 No validity data could be found for VCD.

Results displayed a significantly lower cough severity according to VAS for patients treated with ivy leaf extract compared to the placebo group. This effect was confirmed by BSS and VCD over the treatment period of seven days, and again by VAS over the whole observation period of 14 days. Nevertheless, it is worth noting that cough severity also decreased in the placebo group over the treatment and observation periods. MID for VAS reached 17 mm after three days in the ivy leaf group, and after four days in the placebo group. When analyzing data from each of the five treatment centers separately, no significant difference between the ivy leaf group and placebo group was detected for one center. Treatment compliance was rated “good” because more than 80% of the calculated theoretical intake had been administered to the per-protocol (PP) group. Adverse events (AEs) related to cough, like worsening of cough, middle ear effusion, and sinusitis, were reported for 21 of 181 patients (11.6%; nine in the treament group and 12 in the placebo group).21

The efficacy of an add-on treatment with ivy leaf extract in a syrup formulation (Prospan Hustensaft) on lung function in asthmatic children was investigated in another placebo-controlled clinical study.26 Thirty children (6-12 years of age) who suffered from partial or uncontrolled persistent allergic asthma were enrolled in this randomized, placebo-controlled, double-blind, crossover, monocenter study. The placebo was described as “an inactive, identical flavored, look-alike syrup.” One child withdrew from the study during the first treatment period, and five other children showed treatment compliance below 80%. The treatment group received 70 mg of ivy leaf extract daily for 28 to 30 days. The treatment and placebo periods were separated by a washout phase of 28 to 30 days. At the beginning of the run-in phase, all subjects were adjusted to 400 µg of budesonide (a conventional corticosteroid anti-inflammatory drug) daily, which remained the baseline therapy throughout the whole study. Lung function was evaluated by spirometry and body plethysmography before and after bronchodilation. Additionally, patients answered questionnaires about asthma symptoms and quality of life. The Asthma Control Questionnaire (ACQ) reflects some core asthma symptoms and symptom-related clinical markers of asthma.27 The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) consists of 23 questions that address symptoms, activity limitations, and emotional function.28,29

While evaluating treatment effects according to the primary outcome measures (relative change of FEV1 and MEF75-25 before bronchodilation), no significant effects of ivy leaf extract were observed. Significant changes were presented in absolute change of MEF75-25, MEF25, and VC before bronchodilation. The ACQ score decreased significantly in the placebo group, but not in the treatment group. All other evaluated parameters did not differ significantly. The authors conclude that treatment with ivy leaf extract in addition to an inhaled corticosteroid can lead to a significant improvement in lung function parameters in children with mild, persistent, uncontrolled asthma.26

Mansfeld et al. 30 conducted a randomized, placebo-controlled, double-blind, crossover, monocenter study to analyze the secretolytic and bronchospasmolytic efficacy and safety of ivy leaf extract in a drop formulation (Prospan Hustentropfen) in 28 asthmatic children (4-12 years of age). Discontinuation of treatment was reported for four patients due to intervening diseases. Patients received a daily dose of 35 mg of ivy leaf extract during a treatment period of three days. A washout phase of three to five days separated the treatment and placebo periods. The main objective was the alteration of lung function determined by respiratory resistance, which was significantly reduced in the treatment group compared to the placebo group at the end of treatment (day three). A significant reduction of intrathoracic gas volume (ITGV) was detected in the treatment group relative to placebo, whereas alterations of residual volume (RV) were not significantly different between groups.

Studies with Active Comparators

In a randomized, double-blind, reference-controlled, multicenter study, Cwientzek et al.31 compared the efficacy and safety of two marketed ivy leaf extract drop compositions: Hedelix Hustentropfen (Krewel Meuselbach GmbH; Eitorf, Germany; DER 2.2-2.9:1, extraction solvent: ethanol 50% [v/v], propylene glycol [98:2]) and Prospan Hustentropfen. A total of 590 patients (2-86 years of age) across seven sites with AB were recruited and equally distributed to both treatment groups. Overall, 72 drop-outs were reported (35 in the Hedelix group and 37 in the Prospan group). Study medication dosage was determined according to age. The original drop former of the test product Hedelix was exchanged to permit blinding, and, therefore, the number of drops per mL is different from the marketed product. Hence, it is not possible to calculate the exact daily dose for this group. Children in the Prospan group received a daily dose of 25.2 mg (2-4 years of age), 33.6 mg (4-10 years of age), or 50.4 mg (10 years of age or older) of ivy leaf extract over a seven-day treatment period. The authors acted on the assumption that both products contained equivalent drug contents. In contrast to Prospan drops, Hedelix drops contain an ethanol-free fluid extract.

Efficacy was evaluated by investigators via BSS and by patients via VAS rating. Analysis was separately carried out in the intention-to-treat (ITT) and in the PP datasets. No significant differences between the treatment groups or between the ITT and PP datasets could be determined. BSS decreased by approximately 4.7-4.9 points until day seven. Patients rated the efficacy of ivy leaf extract according to VAS from 0 mm (not at all satisfied) to 100 mm (completely satisfied) with a mean of 78.7 ± 22.9 mm for the Hedelix drops group and 76.4 ± 23.7 mm for the Prospan drops group. AEs were reported in 16 of 590 patients (2.7%), with most of these patients suffering from gastrointestinal issues.31

Unkauf and Friedrich 32 conducted a randomized, prospective, multicenter (number of sites not stated) clinical study that evaluated the efficacy and safety of one cough syrup containing ivy leaf extract (Valverde; authorization holder not declared; DER 3-6:1; ethanol 60% [v/v]) against Prospan Hustensaft in 52 children (0-12 years of age) who suffered from dry and painful or productive cough. The exact dose of both medications was not declared. Duration of treatment was 10 days. Outcomes were measured by VAS and a clinical global impression scale (CGI), which addresses disease severity (CGI item I), change of patient status (CGI item II), and ratio of therapeutic effect to AEs (CGI item III). Moreover, cough characteristics, auscultation (listening to respiratory function via stethoscope), AEs, and lab parameters were evaluated. Since 51 of 52 patients showed an improvement in test criteria of at least 50% within 10 days, the authors concluded an equivalent efficacy of both ivy leaf extract preparations.

The efficacy of ivy leaf extract contained in drops and suppositories (Prospan Hustentropfen and Prospan Hustenzäpfchen, respectively) was compared in 26 children (5-11 years of age) with chronic obstructive respiratory diseases in another randomized, crossover, monocenter study by Mansfeld et al.33 There was no information about dropouts. Patients received a daily dose of 35 mg (drops) or 160 mg (suppositories) of ivy leaf extract over a three-day treatment period. The authors concluded equal efficacy of both formulations in this patient population.

Gulyas et al.34 analyzed the equivalence of an ivy leaf extract cough syrup and a drop formulation (Prospan Hustensaft and Prospan Hustentropfen, respectively) in a randomized, double-blind, crossover setting. The number of treatment sites was not indicated. Twenty-seven children (10-15 years of age) who suffered from chronic obstructive respiratory disease were included, and the authors reported two dropouts. Children received daily doses of 105 mg of ivy leaf extract in the syrup group and 42 mg in the drops group. Treatment duration was 10 days, and both treatments were separated by a washout phase of two to four days. Lung function parameters (FEV1, FVC, VC, PEF, RAW, ITGV, and sRAW) were measured, and results displayed a statistically significant difference from the first day to day 10 of treatment for all parameters in both groups. The authors concluded therapeutic equivalence for both groups and since daily doses differed, they hypothesized that the bioavailability of ivy leaf extract is increased by the addition of alcohol.

Meyer-Wegener et al. 35 conducted a double-blind, monocenter clinical study in which the efficacy of ivy leaf extract cough drops (Prospan Hustentropfen) was compared to ambroxol tablets (product not declared) in 99 patients (25-70 years of age) who suffered from chronic bronchitis. One patient was excluded during the study because of prohibited concomitant conventional drug intake. Each group received drops as well as tablets (one of which was a placebo version) in order to maintain the double-blinding nature. Patients received a daily dose of 42-70 mg of ivy leaf extract or took one ambroxol tablet three times daily, with the corresponding placebo formulation, for four weeks. Lung function parameters were measured each week to determine VC, FVC, FEV1 relative to VC, a peak flow profile, and an auscultation report. Additionally, patients kept a diary. The authors concluded equality of both interventions after the treatment period, since they were not able to detect significant differences in lung function parameters between groups. AEs were reported in 13 of 99 patients. The authors did not provide AE details.

Bolbot et al. 36 compared the efficacy and tolerability of ivy leaf extract (Prospan, undeclared formulation) and ACC (product not declared) for the treatment of children with acute obstructive and non-obstructive bronchitis in an open and multicenter study. Fifty children (2-10 years of age) across two sites were included. There was no information about dropouts. Daily doses were 105 mg of ivy leaf extract or 300-600 mg of ACC (for children 2-6 years of age), or 210 mg of ivy leaf extract or 900-1,200 mg of ACC (for children 7-10 years of age). Treatment started 4.7 days (ivy leaf extract group) or 4.5 days (ACC group) after disease onset and was administered over seven to 10 days. Clinical symptoms, such as cough characteristics, sputum expectoration, shortness of breath, and respiratory pain, were evaluated after seven days and after the full treatment period. In 19 patients in the ivy leaf extract group and 18 patients in the ACC group, external respiration parameters like FVS, FEV1, PEF, MEF25, MEF50, MEF75, and average inhalation weight hour space velocity (AWSV)25-75 also were documented after five days and after the full treatment.

Analysis of disease symptoms showed equal values during the treatment period for both groups. After analyzing the external respiration parameters, the authors concluded a superiority of ivy leaf extract compared to ACC concerning its broncholytic activity. The efficacy of ivy leaf extract was rated as “very good” by 40%, “good” by 56%, and “moderate” by 4% of the children. The efficacy of ACC was rated as “very good” by 12.5%, “good” by 66.7%, and “moderate” by 20.8% of the children. The tolerability of ivy leaf extract was rated as “very good” by 40% and “good” by 60% of the investigators, and the tolerability of ACC was rated as “very good” by 12%, “good” by 64%, “moderate” by 20%, and “poor” by 4% of the investigators.36

Maidannik et al.37 conducted an open, multicenter (two sites) clinical study that addressed the efficacy of an ivy leaf extract cough syrup preparation (Prospan Hustensaft) in relation to ambroxol syrup (product not declared) in children (0-15 years of age) with acute or chronic respiratory disease. In parallel, 30 of the 72 enrolled children suffered from concomitant diseases and partially received antibiotics. There was no information about dropouts. Ivy cough syrup was given to 53 children and ambroxol to 19. The daily dose of ambroxol syrup was not declared, and no precise amount of ivy leaf extract could be derived from the declaration that three teaspoons (for children 1-6 years of age) or six teaspoons (for children 7-14 years of age) of the cough syrup were administered daily. The treatment period was seven to 10 days for acute and 10-14 days for chronic conditions, and medication started three to four days after the onset of illness.

Patient condition was documented once a day, and an evaluation of clinical efficacy according to a four-point scale (excellent, good, poor, no effect) was conducted on days three, seven, and 14. For the Prospan group, no effect was reported in 3.3% of patients and, depending on the assessor, efficacy was rated as 90.1% by physicians and 87.1% by patients or their parents. Additionally, a normalization of leukocyte count after 7 1.5 days for all patients was observed. The authors concluded that the ivy leaf extract preparation had broncholytic activity because the external respiration weight space velocity normalized during the treatment of patients with obstructive abnormalities. No significant difference between treatments was observed in terms of decreasing symptoms of productive cough. More than 50% of patients were cough-free after seven days, and all were cough-free after 14 days in both treatments groups.37

Observational Studies

Schmidt et al.38 conducted two independent open, non-interventional, multicenter (14 sites) clinical studies that analyzed the tolerability and safety of two different formulations of an ivy leaf extract (Hedelix syrup and drops) in children (0-13 years of age) who suffered from acute respiratory catarrh and/or chronic recurrent inflammatory bronchial disease. The syrup formulation was given to 133 children, and the drops were given to 135 children. Fifteen patients were excluded from the study. Children received a daily extract dose of 50 mg (0-1 year of age), 150 mg (1-4 years of age), 200 mg (4-10 years of age), or 300 mg (10-13 years of age) for an average treatment period of 10 days. Tolerability and safety were evaluated via a verbal rating scale by each patient, their caregivers, and physicians. Five AEs were recorded during these studies; four of these were gastrointestinal issues, and one patient suffered from angular cheilitis (lip inflammation) and diaper dermatitis. In 98.2% or 99.2% of patients receiving syrup and 96.9% or 100% of patients receiving drops, a good to very good tolerance was reported at the final visit depending on the respondent, either patient or physician.

Stauss-Grabo et al.39 conducted an observational, multicenter (10 sites) study that evaluated the tolerability of film-coated tablets (Prospan) that contained 25 mg of ivy leaf extract each for the treatment of catarrh of the upper respiratory tract accompanied by cough, chronic bronchitis, COPD, pneumonia, or AB. A total of 331 patients (11-85 years of age) were included, and one dropout was reported. The treatment dose varied. A total of 310 patients received at least seven days of treatment: 113 patients with a twice-daily dose of two tablets, 196 patients with a dose of two tablets three times per day, and one patient with a dose of one tablet three times per day. The overall treatment duration was two to 28 days, with 126 patients receiving two tablets twice per day, 203 patients with a dose of two tablets three times daily, and one patient with one tablet three times per day. The median treatment duration was eight days. Concomitant diseases were reported for 20 patients. No serious AEs were reported, but one patient suffered from nausea during treatment. Tolerability was rated as “very good” or “good” by 95.4% of patients and 98.5% of physicians. Patient compliance was rated as “good” by 99.1% of the physicians and “moderate” by 0.9% of the physicians. The authors concluded that the ivy leaf extract that was investigated is safe and very well tolerated in the studied population.

Fazio et al.40 demonstrated the tolerability and safety of an ivy cough syrup formulation (Prospan Hustensaft) in an open, multicenter (3,287 sites) post-marketing study with 10,562 included patients (0-98 years of age) recruited by physicians in 11 Latin American countries. Because they did not participate in follow-up visits, 905 patients were not evaluated. Among the patients were 5,181 children (0-14 years of age) with acute or chronic bronchial inflammatory disease associated with hypersecretion of mucus and productive cough (which is frequently associated with an infectious agent), and patients with cough alone. The daily doses of ivy leaf extract were 52.5 mg (for children 0-5 years of age), 105 mg (6-12 years of age), and 105-157.5 mg (older than 12 years of age) for a seven-day treatment period. Concomitant conventional drug intake was reported for 5,865 patients, whereas 3,795 patients received antibiotics. AEs were reported in 2.1% of all patients and in 1.2% of children. These AEs were mainly gastrointestinal issues and allergic skin symptoms. Additionally, these patients reported dry mouth and thirst, anorexia, eructation (belching), stomatitis, anxiety, headache, drowsiness, palpitation, sweating, and other AEs. The majority (96.6%) of the study population tolerated the therapy well. The occurrence of AEs increased when conventional drugs, especially antibiotics, were used. 

A retrospective, multicenter (310 sites) data acquisition presented by Kraft 41 evaluated the tolerability of an ivy leaf extract cough syrup (Prospan Hustensaft) in 52,478 children (0-12 years of age) with symptomatic respiratory diseases. The mean drug dose was 364 mg (1-5 years of age), 653 mg (6-9 years of age), and 710 mg (10 years of age or older). Among this population, 115 AEs were reported, with about 77% suffering from gastrointestinal issues and about 18% exhibiting allergic skin rashes (exanthema and urticaria). 

Several other post-marketing surveillance studies that focused on the treatment of different respiratory diseases with diverse formulations of ivy leaf extracts present an overall “good” to “very good” tolerability stated by investigators and patients.42-45 AEs reported in these studies were gastrointestinal issues and allergic exanthema.43-45 Besides allergic exanthema and urticaria, other allergic side effects of ivy leaf formulations, such as dyspnea, have also been reported.14 Some studies reported low numbers of dropouts due to a lack of therapeutic efficacy.40,44,46

Discussion

Clinical research on the efficacy and safety of ivy leaf preparations for the therapy of respiratory diseases dates back to the 1950s.18,19 The clinical studies reviewed here were published between 1993 and 2016. Since the underlying study designs vary, we separated all reviewed studies into two major groups: controlled and non-controlled studies. An adequate study design that includes an appropriate control is a prerequisite to determine the efficacy of a treatment, and, therefore, controlled studies were evaluated according to their relevance for safety and efficacy, whereas non-controlled studies were reviewed to assess only information on treatment safety. Besides the absence of a control, observational and non-interventional studies of marketed herbal medicinal products that contain ivy leaf extract are open data collections in practice; this study design is not capable of providing a strong basis to evaluate the overall efficacy. Since acute respiratory diseases are mostly of a self-limiting nature, the difficulty of finding an adequate study design must be acknowledged when evaluating data reliability. In the context of this self-limiting nature, clinical investigations can only prove a more rapid healing in contrast to controls.

Clinical Efficacy

Acute Respiratory Disease (Acute Cough)

Just two of the 19 reviewed studies were carried out in a randomized controlled design; one was placebo-controlled21 and the other was reference-controlled.31 Both determined cough severity via BSS and, based on the results obtained, the authors were able to conclude an improvement in the treatment groups within seven days of treatment.

Schaefer et al.21 demonstrated a BSS improvement of 8.4 in the treatment group, compared to 5.8 in the placebo group after seven days of treatment, but in this study a 20% improvement according to BSS in the treatment group was also shown in relation to a 10% improvement in the placebo group after 48 hours. Although the results of this study present the only data on efficacy in acute cough with a certain level of evidence, it also suffers from design flaws, like the questionable blinding and application of statistical methods. BSS seems to be the only validated score used in the Schaefer et al. study (scores like VAS, VCD, and GEA are not considered validated assessment tools).

Since Cwientzek et al.31 did not present absolute data, it is difficult to assess efficacy, especially according to the known BSS improvement for the placebo group from the Schaefer et al.21 study. Moreover, it is difficult to determine comparability of drug doses for the products in this study, because a calculation of the exact drug dose for the Hedelix group is not possible, since the original drop former was exchanged for the test product to permit blinding. Even though both studies included more patients than most other studies, statistically verified patient numbers would be desirable.

The definition of an adequate reference control for the determination of efficacy is a stumbling block. Bolbot et al. concluded that the ivy leaf extract (Prospan) and ACC had equal mucolytic activity.36 The mucolytic efficacy of ACC and other mucolytic agents has been reported, but the clinical benefits are a matter of scientific debate.47 Therefore, reporting an equal effect of ivy leaf extracts and standard mucolytics is not sufficient without simultaneously presenting superiority against placebo in the same setting. Moreover, the treatment started 4.5 to 4.7 days after disease onset in this study, which is late in the context of this self-limiting disease. Bolbot et al. also reported that ivy leaf extract (Prospan) had superior spasmolytic activity, as determined by spirometric analysis. Although this effect is reasonable, performing spirometric assessments with young children is challenging. Moreover, patient selection criteria for spirometric analysis are non-transparent and therefore permit selection bias.

Chronic Respiratory Disease

Among the 19 reviewed clinical studies, six focused on chronic respiratory diseases, five of which were conducted in a randomized and controlled study design. Two of the six studies evaluated the efficacy of ivy leaf extract in children who suffered from chronic obstructive respiratory disease.33,34 Both studies were randomized, controlled, crossover studies that compared the efficacy of two ivy leaf extract (Prospan) formulations, and both had severe study design flaws according to current clinical trial design standards. Definitions of chronic respiratory diseases have changed over the years, and different opinions about their classification still exist.8,48 According to the current definition of COPD, for example, the disease rarely affects children.12 No effective conclusion about the efficacy of ivy leaf extract in patients suffering from COPD can be drawn from the evaluation of the endpoints presented in these studies, since inclusion criteria did not match the current definition of COPD. Daily dose and/or route of administration of the diverse ivy leaf extract formulations (e.g., syrup, drops, tablets, or suppositories) compared here clearly differ. It would have been necessary to either administer the same doses or prove an equal “bioavailability” of unequal doses due to different routes of administration. (In this context, the term “bioavailability” is not accurate when talking about an extract formulation that contains a multitude of ingredients.) Moreover, the washout phase was relatively short (two to four days) in both studies, so carryover effects may have played a role. To evaluate efficacy from these data is challenging due to missing placebo control, low patient numbers, and concomitant conventional drug intake.

Another randomized, double-blind, monocenter, ambroxol-controlled study evaluated the efficacy of an ivy leaf extract (Prospan) for the treatment of chronic bronchitis.35 The authors concluded equivalence for both treatments since they were not able to detect significant differences in spirometric, auscultation, or diary analyses. Unfortunately, this publication did not present any details about the exact dose of the active comparator ambroxol. The challenge with standard mucolytic reference controls was described previously. Consequently, a beneficial bronchospasmolytic effect for the therapy of chronic obstructive bronchitis was not observed with either of the two preparations.

In two studies, the efficacy of an ivy leaf extract (Prospan) in asthmatic children was assessed.26,30 Both were randomized, placebo-controlled, double-blind, crossover studies in which body plethysmography and spirometry were used to determine improvements in lung function. Mansfeld et al.30 found a statistically significant reduction of RAW and ITGV after three days of therapy with ivy leaf extract. Spirometric parameters did not differ significantly. The PP analysis included only 24 patients. The authors presented insufficient information about statistical methods. A treatment period of three days in a chronic, paroxysmal obstructive disease is short, and a single visit is not sufficient to assess treatment efficacy since asthma is characterized as an alternating daily condition. Moreover, a washout phase of three to five days may result in confounding carryover and treatment effects.

Zeil et al.26 included 30 asthmatic children (6-12 years of age), although six protocol violations were reported (20% of the overall study population). Baseline therapy was budesonide, and ivy leaf extract (Prospan) was examined as an add-on therapy to enhance lung function. Partially improved lung function after four weeks of treatment was determined. Data were obtained according to the ITT analysis, without declaring the procedure for dropout values. Moreover, a drawback of ACQ is the rating period since patients evaluate symptoms from the previous seven days; a shorter period or daily rating would be more desirable to evaluate variable asthma symptoms.27 Because of the non-crossover analysis and the small study population, the data presented are not convincing to determine the efficacy of ivy leaf extract as an add-on therapy for asthmatic children. This study concept implicates a risk that budesonide baseline therapy might mask potential advantageous effects of the add-on therapy with ivy leaf extract. This, however, has no bearing on the positive outcome of the study. The changes in absolute lung function parameters may be promising enough to conduct more studies with a larger patient population and more stringent study design to determine a benefit for asthmatic children.

Non-Homogeneous Patient Population (Acute and Chronic Respiratory Disease)

As previously mentioned, the evaluation of treatment effects is especially difficult when diverse patient populations are pooled and analyzed together. In two studies, investigators tried to assess the efficacy of ivy leaf extracts (Prospan and Valverde) for the therapy of acute or chronic respiratory diseases,37 or dry and painful or productive cough,32 with small study populations in an open setting. Both studies fail to provide diagnostic details and the exact daily doses of all medications. The authors at least partially justified the efficacy of the therapy with a treatment success of about 50% of patients after seven days.32 This argument is especially controversial when talking about a disease that is self-limiting to some extent. Concomitant diseases and drug intake also were reported in various cases,37 or this information was not presented at all.32 Parameter evaluation was based mainly on invalid scores or verbal ratings. Maidannik et al.37 presented a non-homogenous allocation to treatment groups and treatment duration. Treatment started three to four days after disease onset, which seems to be late and is also confusing, taking the patients with chronic conditions into account.37 Altogether, a conclusion based on evidence-based criteria about any treatment efficacy is difficult with these severe flaws in study design according to current clinical trial standards.

Summary

Most of the controlled clinical studies discussed here in terms of efficacy investigated a similar ivy leaf extract, Prospan, marketed in different formulations. Further details on extract manufacture are not available, and no statements were provided regarding the similarity of extracts used in the products administered apart from extract solvent (ethanol 30% [w/w]) and DER (5-7.5:1). This extract is also listed as extract “a” in the EU HMPC monograph.

A certain degree of efficacy of ivy leaf extract was demonstrated in only one study: a randomized, placebo-controlled, double-blind and multicenter study in adults with acute cough based on a validated score to evaluate AB severity.21The outcome of the study clearly indicates an efficacy of ivy leaf extract in reducing cough severity and, therefore, a benefit in the treatment of acute cough. An additional recording of lung function parameters would have been desirable to corroborate these effects.

Data obtained from all other reviewed studies that focused on AB or obstructive diseases like asthma or COPD were not convincing and did not conclusively establish therapeutic effects in an evidence-based manner. Drawbacks of these studies include non-homogenous patient populations according to diagnosis and/or age,28-31,33-35 concomitant diseases or drug intake,26,36 and lack of appropriate controls. Presenting equivalence of ivy leaf extract and other expectorants that contain ambroxol or ACC is not meaningful when superiority over placebo is not established in the same study design.

Assessing cough severity is challenging. Validated scores are essential to obtain reliable results. BSS is a validated method to assess AB severity.22 Other scores used are not valid and, therefore, less useful in support of clinical effects.

One study was designed to compare different formulations (suppositories versus drops) of ivy leaf extracts without discussing the possible impact of these different routes of administration in terms of systemic availability of putative active constituents in the extract.33

The relevance of data supplied by many studies suffers from low numbers of patients or investigation sites.26,30,32,33,36 Results presented in these studies can serve only as a lead; more robust evidence might be established in clinical trials with larger patient populations. Another drawback is the open study design.33,36 In most studies, no indication regarding blinding of placebo and active treatment was given.

Clinical Safety

Tolerability

The tolerability of ivy leaf extracts (Prospan and Hedelix) in formulations tested was overall rated “good” to “very good” in the vast majority of cases.31,33,36,38-40 Discontinuation of treatment was reported for four patients due to intercurrent diseases.30

Adverse Events

None of the reported AEs were classified as serious. AEs occurred in one of 330,39 five of 272,38 16 of 590,31 and 115 of 52,47841 patients. Most of the AEs reported were gastrointestinal side effects, but allergic reactions were also described. In one study, worsening of cough, middle ear effusion, and sinusitis were reported in 21 of 181 patients.21 Meyer-Wegener et al. reported AEs in 13 of 99 patients, but did not disclose any details.35

Two observational studies are of special interest, because a large number of patients was evaluated and relatively high daily doses of ivy leaf extract (Prospan) were administered.40,41 The HMPC herbal monograph recommends a daily extract dose of 24-36 mg (2-5 years of age), 33-70 mg (6-11 years of age), or 45-105 mg (12 years of age or older).14 Fazio et al. described daily extract doses of 52.5 mg (0-5 years of age), 105 mg (6-12 years of age), or 105-157.5 mg (12 years of age or older),40 and Kraft described mean daily drug doses of 364 mg (1-5 years of age), 653 mg (6-9 years of age), or 710 mg (10 years of age or older).41 AEs were reported in 203 of 9,65740 and 115 of 52,478 patients,41 respectively. These AEs were also mainly gastrointestinal disorders and allergic skin symptoms. Besides these, Fazio et al.40 reported AEs such as dry mouth and thirst, anorexia, eructation, stomatitis, anxiety, headache, drowsiness, palpitation, sweating, and others. AEs led to discontinuation of therapy in 46 cases and were increased when additional drugs, especially antibiotics, were prescribed. Overall, 388 patients discontinued treatment, mostly because of improvement (186 patients), lack of efficacy (76 patients), or worsening (39 patients). One drawback of this study is the high dropout rate (905 patients). This might have an effect on the number of AEs reported. Furthermore, the patient population was non-homogenous in terms of age and symptoms, and concomitant drug intake was recorded in 60.7% of patients.40

Contraindications and Precautions

To limit the risk of AEs, some precautions should be considered. According to European regulations, children younger than two years of age should not receive secretolytic agents because of the risk of aggravation of respiratory symptoms. Medical diagnosis is necessary before therapy in cases of recurrent or persistent cough in young children (2-4 years of age) and if dyspnea, fever, or purulent sputum occur. If hypersensitivity to substances originating from the Araliaceae family is known, alternative treatments should be used. The concomitant use of opioids or active ingredients derived from opioids, like codeine or dextromethorphan, is not recommended without medical advice. Due to the prevalence of gastrointestinal side effects, patients with gastritis or gastric ulcers should be treated with care. Since there are no sufficient safety data, ivy leaf extracts should not be used during pregnancy or lactation. Children under six years of age should not receive liquid ivy leaf extract preparations with a DER of 1:1 and ethanol 70% (v/v) as the extraction solvent because of the alcohol content. Overdose may induce nausea, vomiting, diarrhea, and/or agitation.14

Aggression and diarrhea after an accidental intake of an ivy leaf extract (reported DER 4-8:1; extraction solvent: ethanol 30% (m/m)) corresponding to 1.8 g of herbal substance was reported for one four-year-old child.15

Conclusion

Ivy leaf extracts have shown effects in vitro that may correspond to secretolytic and bronchospasmolytic clinical effects. Many clinical studies have been carried out to confirm these effects. Unfortunately, most of these studies lacked an appropriate design to support the proposed effects in an evidence-based manner. Regardless of their evidence level, most of the reviewed clinical studies determining the efficacy and/or safety of ivy leaf extracts for the therapy of respiratory diseases accompanied by cough are of low quality due to significant design flaws according to current standards.

However, one of the 19 reviewed studies was performed in a randomized, placebo-controlled, multicenter, and double-blind design. The study was conducted with Prospan Hustenliquid. Based on the results obtained, the authors were able to convincingly demonstrate an effective reduction of cough severity in adults who suffered from acute cough, although some of the applied scores are of debatable validity to evaluate bronchitis severity. While results should be confirmed in further studies with appropriate design, these data strongly suggest a secretolytic effect in acute cough.

The efficacy of ivy leaf extracts in chronic respiratory diseases is still unclear, and we could not find more than a promising lead while reviewing clinical data. No serious AEs were described. Since AEs were rare and not serious, mostly related to gastrointestinal disorders or allergic reactions, we conclude that the short-term (up to seven days) application of the investigated ivy leaf extracts discussed in this article presents a negligible risk in the treatment of acute respiratory diseases accompanied by cough. Further research should include the objective of exacerbation prophylaxis to gain more helpful information about potential benefits for patients who suffer from chronic respiratory diseases.

Ann Reckhenrich, PhD, joined i.DRAS GmbH as a scientific and regulatory affairs expert in 2016. She has a degree in pharmacy from the University of Bonn in Bonn, Germany, and a degree in journalism from the Free School of Journalism in Berlin, Germany.

Andrea Klüting, PhD, joined i.DRAS GmbH in 2007 and is the head of the pharmacology team and senior expert in scientific and regulatory affairs. She has a degree in pharmacy and completed the postgraduate master’s course “Drug Regulatory Affairs,” both at the University of Bonn.

Markus Veit, PhD, is the managing director of i.DRAS GmbH and Alphatopics GmbH. He is also an adjunct professor of pharmaceutical biology with positions at the University of Frankfurt in Frankfurt, Germany, and the University of Florida in Gainesville, Florida.

Disclosures

Although this article has partially been financed by Anklam Extrakt GmbH (Anklam, Germany), a manufacturer of botanical extracts that includes ivy leaf extracts, it was written independently and, therefore, the authors declare no conflict of interest.

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