Matthias Kröz

Remedies Containing Asteraceae Extracts: A Prospective Observational Study of Prescribing Patterns and Adverse Drug Reactions in German Primary Care

AbstractBackground: The use of complementary therapies by patients has increased over the past 20 years, both in terms of self-medication and physician prescriptions. Among herbal medicines, those containing extracts of Asteraceae (Compositae), such as Echinacea spp., Arnica montana, Matricaria recutita and Calendula officinalis, are especially popular in the primary-care setting. However, there remains a gap between the growing acceptance of these remedies and the lack of data on their safety. Objective: The aim of this study was to analyse prescribing patterns and adverse drug reactions (ADRs) for Asteraceae-containing remedies in Germany. Methods: Primary-care physicians, all of whom were members of the German National Association of Anthroposophic Physicians were invited to participate in this prospective, multicentre, observational study. During the study period (September 2004 to September 2006), all prescriptions and suspected ADRs for both conventional and complementary therapies were documented using a web-based system. The study centre monitored all ADR reports and conducted a causality assessment according to Uppsala Monitoring Centre guidelines. Relative risks (RRs) and proportional reporting ratios (PRRs) were calculated. Results: Thirty-eight physicians, 55% of whom were general practitioners and 45% were specialists, fulfilled the technical requirements and were included in the investigation. Because documenting all ADRs (i.e. serious and non-serious) was time consuming, only a subgroup consisting of seven physicians agreed to report nonserious in addition to serious ADRs. During the study period, a total of 50 115 patients were evaluated and 344 ADRs for conventional and complementary remedies were reported. Altogether, 18 830 patients (58.0% female, 60.3% children) received 42 378 Asteraceae-containing remedies. The most frequently prescribed Asteraceae was Matricaria recutita (23%), followed by Calendula officinalis (20%) and Arnica montana (20%). No serious ADRs for Asteraceae-containing remedies were reported. In the analysis of the subgroup of seven physicians who also documented nonserious ADRs, 11 nonserious ADRs for Asteraceae-containing remedies occurred in 6961 patients, resulting in an RR of 0.13 (95% CI 0.07, 0.23). The majority of reported ADRs for Asteraceae-containing remedies were classified as uncommon. A subgroup analysis comparing phytotherapeutic and homoeopathic preparations did not reveal any relevant differences. The PRR for Asteraceae-containing remedies with respect to all other prescriptions was 1.7 (95% CI 1.0, 2.0) for the system organ class ‘skin and subcutaneous tissue disorders’ (six ADRs) and 1.0 (95% CI 0.3, 3.6) for ‘gastrointestinal disorders’ (three ADRs). Neither result was significant according to the PRR criteria developed by Evans et al. Conclusion: This is the first study to provide a systematic overview of prescribing patterns and ADRs for Asteraceae-containing remedies in the German primary-care sector. Asteraceae-containing remedies were used frequently in this context, especially among children. Our results indicate that treatment with Asteraceae-containing remedies is not associated with a high risk of ADRs.

Validation of the German version of the Cancer Fatigue Scale (CFS-D).

Fatigue is a very important factor determining the quality of life in patients with malignancies. Cancer fatigue occurs with anaemia, during and after chemo- or radiotherapy and in patients with advanced tumours. The Cancer Fatigue Scale (CFS) is a three-dimensional inventory with 15 items which was originally developed in Japan. We present the results of a validation study of the German version (CFS-D) of this instrument. The CFS-D was administered to 114 participants in a matched-pair study. In total, 57 (41 women) of the participants had malignant conditions, and 57 (41 women) were healthy volunteers. The Fatigue Numerical Scale was used to test convergence. The physical and performance status of the cancer patients was assessed by the Karnofsky-Index. Criteria for testing multidimensionality were the Hospital Anxiety and Depression Scale, and the questionnaire on autonomic regulation. We generated a three-dimensional inventory of the CFS-D with the subscales physical fatigue/vitality, cognitive and affective fatigue. The reliability results for the complete scale: Cronbachs alpha: r(alpha) = 0.94, retest reliability: r(rt) = 0.82. The convergence criteria correlate between r = 0.44-0.65 (all P < 0.001). The CFS-D is highly reliable and has construct validity in relation to other measures.

Validation of a questionnaire measuring the regulation of autonomic function

BackgroundTo broaden the range of outcomes that we can measure for patients undergoing treatment for oncological and other chronic conditions, we aimed to validate a questionnaire measuring self-reported autonomic regulation (aR), i.e. to characterise a subjects autonomic functioning by questions on sleeping and waking, vertigo, morningness-eveningness, thermoregulation, perspiration, bowel movements and digestion.MethodsWe administered the questionnaire to 440 participants (♀: N = 316, ♂: N = 124): 95 patients with breast cancer, 49 with colorectal cancer, 60 with diabetes mellitus, 39 with coronary heart disease, 28 with rheumatological conditions, 32 with Hashimotos disease, 22 with multiple morbidities and 115 healthy people. We administered the questionnaire a second time to 50.2% of the participants. External convergence criteria included the German version of the Hospital Anxiety and Depression Scale (HADS-D), a short questionnaire on morningness-eveningness, the Herdecke Quality of Life Questionnaire (HLQ) and a short version questionnaire on self-regulation.ResultsA principal component analysis yielded a three dimensional 18-item inventory of aR. The subscales orthostatic-circulatory, rest/activity and digestive regulation had internal consistency (Cronbach-α: rα = 0.65 – 0.75) and test-retest reliability (rrt = 0.70 – 85). AR was negatively associated with anxiety, depression, and dysmenorrhoea but positively correlated to HLQ, self-regulation and in part to morningness (except digestive aR) (0.49 – 0.13, all p < 0.05).ConclusionAn internal validation of the long-version scale of aR yielded consistent relationships with health versus illness, quality of life and personality. Further studies are required to clarify the issues of external validity, clinical and physiological relevance.

Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients

Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.

Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma A Retrospective Analysis

Pancreatic carcinoma remains one of the main causes for cancer-related death. Intratumoral application of anticancer agents is discussed as a promising method for solid tumors such as pancreatic cancer. Endoscopic ultrasound provides a good tool to examine and treat the pancreas. European mistletoe (Viscum album L) is a phytotherapeutic commonly used in integrative oncology in Central Europe. Its complementary use seeks to induce immunostimulation and antitumoral effects as well as alleviate chemotherapeutic side effects. Intratumoral mistletoe application has induced local tumor response in various cancer entities. This off-label use needs to be validated carefully in terms of safety and benefits. Here we report on 39 patients with advanced, inoperable pancreatic cancer, who received in total 223 intratumoral applications of mistletoe, endoscopic ultrasound guided or under transabdominal ultrasound control. No severe procedure-related events were reported. Adverse drug reactions were mainly increased body temperature or fever in 14% and 11% of the applications, respectively. Other adverse drug reactions, such as pain or nausea, occurred in less than 7% of the procedures. No severe adverse drug reaction was recorded. Patients received standard first- and second-line chemotherapy and underwent adequate palliative surgical interventions as well as additive subcutaneous and partly intravenous mistletoe application. A median survival of 11 months was observed for all patients, or 11.8 and 8.3 months for stages III and IV, respectively. Due to the multimodal therapeutic setting and the lack of a control group, the effect of intratumoral mistletoe administration alone remains unclear. This retrospective analysis suggests that intratumoral-applicated mistletoe might contribute to improve survival of patients with pancreatic cancer. In conclusion, the application is feasible and safe, and its efficacy should be evaluated in a randomized controlled trial.

Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study

Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this “off-label” application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended.

Multimodal Therapy Concept and Aerobic Training in Breast Cancer Patients With Chronic Cancer-Related Fatigue

Hypothese: Cancer-related fatigue (CRF) and sleep disorders are some of the most wearing and common symptoms in disease-free breast cancer patients (BC). Aerobic training (AT) is the treatment with the best available evidence, even though it seems to be insufficient with regards to improvements in cognitive fatigue. We introduced a new multimodal therapy concept (MM) consisting of psycho-, sleep-education and new approaches based on anthroposophic medicine such as eurythmy and painting therapy. Study design: This pilot study will test the implementation of MM and yield first results of the MM and AE in our centres. Methods: 31 out of 34 patients suffering from BC and CRF were fully assessed in a ten-week intervention study. 21 patients chose MM and 10 decided on AT. CRF was measured with the help of the Cancer Fatigue Scale (CFS-D), and the global quality of sleep was measured with the Pittsburgh Sleep Quality Index (PSQI). We also captured autonomic regulation (aR) and patients’ satisfaction with questionnaires. Statistical analysis was done with SAS 9.1.3 for windows. Results: The new MM therapy can be implemented with high satisfaction among patients. Significant improvements were found in the MM group with regards to CFS-D, global quality of sleep, sleep efficiency (PSQI), aR and rest/activity regulation compared to baseline (all p<0.05). In the AT group aR orthostatic-circulatory and rest/activity regulation improved significantly (p<0.05), too. However, no improvement in cognitive fatigue was seen in either group. Conclusion: The multimodal therapy concept was feasible and improved cancer fatigue, sleep quality, autonomic and rest-/activity regulation in breast cancer patients. It may therefore constitute a valuable treatment option in addition to aerobic training for BC patients with CRF. A further study with larger sample size needs to be carried out to assess the efficacy of combined multimodal-aerobic therapy.

Entwicklung eines Fragebogens zur endogenen Regulation – ein Beitrag zur Salutogeneseforschung

Development of a Questionnaire for Endogenous Regulation – a Contribution for Salutogenesis Research Introduction: Objective of this study was to develop a questionnaire for endogenous regulation (eR) and to evaluate its relevance in clinical and preventive medicine. The inventory included items about sleeping and waking, orthostatic regulation, thermoregulation, and circadian well-being. Methods: 158 age-matched women with diabetes (1/2, n = 53), breast cancer (n = 52) and healthy controls (n = 53) filled in the Havelhöhe constitutional questionnaire (HKF1.0), and a 24-h-Oxford-FD3-ECG was recorded. Results: We developed a twelve-items scale for eR, which is according to test theory an objective and reliable instrument (Cronbach-α: rα = 0.71, retest reliability: rt = 0.83). The validity analysis confirmed that the breast cancer and diabetic group show a lower eR than the control group (both p < 0.001). Furthermore, high eR is correlated with a ‘rare tendency to feel quite low’, ‘less allergies’, ‘less period pains’, and a ‘shorter duration of breast cancer’. Therefore eR can be regarded as a marker for health and well-being. High eR correlates as well with personality traits as morningness, ‘needing less time for thinking through’, ‘being less unsure at important decisions’, and ‘being less confidential’. We can show first correlations between eR and the rhythmical marker ‘nightly pattern predominance’. With both methods we are achieving for women until 60 years a satisfying discrimination between breast cancer and healthy individuals. Conclusions: We are achieving a first validation of our scale of endogenous regulation. Further studies for the evaluation of the conceptual, clinical, rehabilitative, and preventive medicine relevance of eR are necessary.

Use and Safety of Intratumoral Application of European Mistletoe (Viscum album L) Preparations in Oncology

Background. Intratumoral (IT) injection of European mistletoe (Viscum album L) preparations might induce local tumor response through combined cytotoxic and immunomodulatory actions of the preparations. Although promising in vitro and in vivo data, along with clinical case studies suggest the need for validation of this hypothesis in prospective trials, the safety of IT mistletoe injections has yet to be thoroughly assessed. Methods. The present study summarizes the practice and safety of off-label IT mistletoe therapy within the Network Oncology, a conjoint clinical registry of German hospitals and outpatients specialized in anthroposophic and integrative medicine. Demographic, diagnosis and treatment data of cancer patients who received IT mistletoe applications between 2007 and 2013 were assessed. Suspected adverse drug reactions (ADRs) were analyzed in terms of type, frequency, severity, seriousness and potential risk factors. Results. A total of 123 cancer patients received 862 IT mistletoe injections (preparations from Abnoba, Helixor and Iscucin). The most commonly applied preparations were Abnoba viscum Fraxini (71 patients) and Helixor Mali (54 patients). Of the total patients, 26 patients (21.1%) experienced 74 ADRs. All ADRs were in response to either Abnoba viscum Fraxini (25.4% of exposed patients) or Helixor Mali (18.5% of exposed patients). ADRs were mostly body temperature or immune related and of mild (83.8%) or moderate (14.9%) intensity. Only one possible ADR was described as severe (hypertension) and no serious ADRs occurred. The frequency of ADRs to IT mistletoe injections was 3 times and 5 times higher than has previously been found for subcutaneous and intravenous applications of mistletoe, respectively. Conclusion. IT injection of mistletoe preparations resulted in a relatively high frequency of ADRs. Nearly all ADRs were mild to moderate however, and no serious ADRs occurred. Furthermore, it is possible that immune-related ADRs such as pyrexia and local inflammatory reactions might be critical for tumor response. In light of these results, IT mistletoe therapy seems to be safe and prospective trials are recommended.

Evaluation of prescribing patterns in a German network of CAM physicians for the treatment of patients with hypertension: a prospective observational study

BackgroundThe management of hypertension is a key challenge in modern health systems. This study aimed to investigate hypertension treatment strategies among physicians specialized in complementary and alternative medicine (CAM) in Germany by analysing prescribing patterns and comparing these to the current treatment guidelines issued by the German Hypertension Society.MethodsIn this prospective, multicentre observational study, which included 25 primary care physicians specialized in CAM treatment, prescriptions and diagnoses were analysed for each consecutive hypertensive patient using routine electronic data. Data analysis was performed using univariate statistical tests (Chi square test, Cochran-Armitage trend test). Multiple logistic regression was used to determine factors associated with antihypertensive medication.ResultsIn the year 2005, 1320 patients with 3278 prescriptions were included (mean age = 64.2 years (SD = 14.5), 63.5% women). Most patients were treated with conventional antihypertensive monotherapies (n = 838, 63.5%). Beta-blockers were the most commonly prescribed monotherapy (30.7%), followed by ACE inhibitors (24.0%). Combination treatment usually consisted of two antihypertensive drugs administered either as separate agents or as a coformulation. The most common combination was a diuretic plus an ACE inhibitor (31.2% of dual therapies). Patient gender, age, and comorbidities significantly influenced which treatment was prescribed. 187 patients (14.2%) received one or more CAM remedies, most of which were administered in addition to classic monotherapies (n = 104). Men (OR = 0.66; 95% CI: 0.54-0.80) and patients with diabetes (OR = 0.55; 95% CI: 0.42-0.0.73), hypercholesterolaemia (OR = 0.59; 95% CI: 0.47-0.75), obesity (OR = 0.74; 95% CI: 0.57-0.97), stroke (OR = 0.54; 95% CI: 0.40-0.74), or prior myocardial infarction (OR = 0.37; 95% CI: 0.17-0.81) were less likely to receive CAM treatment.ConclusionsThe large majority of antihypertensive treatments prescribed by CAM physicians in the present study complied with the current German Hypertension Society treatment guidelines. Deviations from the guidelines were observed in one of every seven patients receiving some form of CAM treatment.