Abstract
What is already known about this subject
In general, use of herbal remedies and supplements is constantly rising in the western population and this may be potentially dangerous due to adverse effects and drug–herb interactions.
All information up to now has been derived from the general population or outpatients.
There are no publications on the rate of consumption of herbals in inpatients, or the awareness of the medical team of this fact.
What this study adds
Approximately 25% of patients hospitalized in internal medicine wards consume some kind of herbal or dietary supplement.
Consumption is associated with higher income, nonsmoking and benign prostatic hypertrophy.
The medical team was aware of the consumption in only 23% of the cases, and all drug–herbal interactions which we discovered were missed by the medical team.
Aims
Herbal remedies may have adverse effects and potentially serious interactions with some commonly prescribed conventional medications. Little is known about consumption of herbal remedies and dietary supplements by hospitalized patients. The aim was to evaluate the rate of consumption and characterize the patients hospitalized in internal medicine departments who consume herbal remedies and dietary supplements. Also, to assess the medical teams' awareness and assess the percentage of patients with possible drug–herb interactions.
Methods
Patients hospitalized in the medical wards of two hospitals in Israel were interviewed about their use of herbal remedies or dietary supplements. The medical records were searched for evidence that the medical team had knowledge of the use of herbal remedies or dietary supplements.
Results
Two hundred and ninety-nine hospitalized medical patients were interviewed. Of the participants, 26.8% were herbal or dietary supplement consumers (HC). On multivariate analysis the only variates associated with herbal or dietary supplement consumption were the hospital [odds ratio (OR) 2.97, 95% confidence interval (CI) 1.29, 6.52], income (OR 0.39, 95% CI 0.15, 1.05), smoking habits (OR 0.17, 95% CI 0.05, 0.55) and benign prostatic hypertrophy (OR 4.64, 95% CI 1.3, 16.5). Ninety-four percent of the patients had not been asked specifically of herbal consumption by the medical team. Only 23% of the hospital's medical files of the HC patients had any record of the use of herbal or dietary supplements. Seven possible drug–herbal interactions were encountered (7.1%). The most serious was an interaction between camomile tea and ciclosporin.
Conclusions
Herbal remedy consumption is common amongst patients hospitalized in internal medicine wards and is often overlooked by the medical team. Patients and doctors should be more aware of the possible adverse effects and of the potential of herb–drug interactions.
Keywords: dietary supplements, drug interactions, herbal medicine, herb-drug interactions, inpatients, internal medicine
Introduction
Medical patients are treated with multiple drugs for a variety of diseases. Most of these drugs are prescribed by physicians, but often include herbal remedies and dietary supplements bought over the counter at pharmacies and health stores. Of the American adult population, 14–16% use herbal supplements often concomitantly with prescribed medications [1]. A study of patients visiting family medicine practices in Israel has shown that 36% had used some type of complementary medicine during the past year. Of these patients, 67% used herbal remedies and 49.5% used these remedies simultaneously with conventional medicine [2].
Herbal remedies are efficacious in some conditions, but their safety profile has been questioned, as they are seldom standardized and often contain more than one active component. Recently more evidence has accumulated to the effect that, apart from their adverse effects, some of the popular herbal remedies interact with commonly prescribed conventional medications and may cause serious adverse effects.
Interactions between conventional drugs are relatively easy to detect, once suspected, but interaction with herbal remedies is seldom taken into account by the medical team for several reasons. First, western-trained physicians lack knowledge of herbal medicine [3–5]; second, compositions of herbal drugs may be inconsistent. Herbal remedies are often unaccounted for by the patient, who does not relate to these remedies as ordinary medications, and are often missed by the medical professional, who fails to inquire about these drugs [6].
Little is known about consumption of herbal remedies or dietary supplements amongst hospitalized patients, so we planned this study with the following objectives: (i) to characterize the patients who consume herbal remedies or dietary supplements who are hospitalized in internal medicine departments; (ii) to evaluate the rate of consumption of herbal remedies or dietary supplements amongst patients hospitalized in internal medicine departments; (iii) to evaluate the association, if any, between consumption of herbal remedies or dietary supplements and major diagnosis leading to hospitalization; (iv) to assess the medical teams' awareness of herbal or dietary supplement consumption; and (v) to assess the percentage of patients with possible drug–herb interactions.
Methods
Two hundred and ninety-nine patients hospitalized during August through December of 2005 in the medical wards of two hospitals in Israel were enrolled, after giving informed consent.
Patients were enrolled if they were able to answer the questionnaire or if a primary caregiver was present and could answer the questionnaire. The investigating team consisted of a medical doctor, three pharmacists and a registered nurse. Patients were interviewed with a standardized questionnaire as to their medical history and chronic medications, and specifically about herbal and alternative remedies or dietary supplements. Herbal and alternative remedies were defined as remedies not recognized as conventional medications, comprised of plant or other natural extracts. Dietary supplements were defined as vitamins and minerals added to the patient's diet. Patients on herbal remedies were questioned on the date of initiation of the treatment, indication and person prescribing the remedy. Furthermore, they were questioned about the interest of the medical team at home and at hospital in these supplements.
Data were obtained from the medical files as to the reason for hospitalization and all other current medical diagnoses. The medical records were searched for any evidence that the medical team or family doctor had knowledge of the supplement.
The herbal remedies and dietary supplements were all identified and recorded by the interviewer as to the name, content and quantities or concentration of the active component.
Possible interactions between medications and herbal medicines were reviewed using customary literature sources such as the Micromedex Health Care Series [7] and the Martindale Complete Drug Reference [8]. The medical team was informed of any significant interactions that were discovered.
The local Helsinki committees of both hospitals approved the study.
Statistical methods
This study was a survey, or cross-sectional study. The distribution of disease types and herbal or conventional medications was obtained using statististical distribution tables, graphs and statistical measurements. χ2 test and Fisher's exact test were used to examine and assess possible associations between herbal consumption and other factors such as major or previous medical diagnoses and medications. The multivariate logistic regression model was used to assess the relation between medical and socioeconomic factors and the consumption of herbal remedies and dietary supplements.
Sample size calculation
This was a pioneering study, and we lacked prior information on the consumption of herbals or dietary supplements, especially amongst hospitalized patients, and had no appropriate estimate of the usual parameters used in calculating the sample size. It was therefore decided that the sample size should be as large as possible. The estimated number of patients treated in the internal medicine wards at any given time point in Assaf Harofeh Medical Centre, the larger hospital, is about 300. Hence, our base sample size was 300 patients, taking into consideration that after exclusions the number of intent to treat will be lower.
Results
Patients (n = 299) hospitalized for various reasons in the medical wards of two hospitals in Israel were enrolled. Of these, 199 were enrolled from the three medical wards of the Haemek Medical Centre in Afula (a 450-bed, peripheral hospital in the north-east of Israel, serving a mixed urban and rural population of approximately 500 000 people and affiliated to the Bruce Rappaport Medical School of The Technion) and 100 were enrolled from the seven medical wards of the Assaf Harofeh Medical Centre (an 800-bed hospital in central Israel serving a mixed urban and rural population of 440 000, affiliated to the Tel Aviv University Medical School).
General characteristics of participants (Table 1)
Of participants, 62.5% were male; approximately half of the herbal consumers (HC) were female, meaning that females were more likely than males to be HC (34.8% of all females vs. 21.9% of all males, P = 0.021).
Herbal consumption was associated with the family status of the participants. Widowers tended to consume herbal supplements [18.8% HC vs. 9.1% nonconsumers (NC)], whereas bachelors tended not to do so (3.8% HC vs. 11.9% NC) (P = 0.033). Seventy-three percent of the participants were willing to disclose their monthly income. NC were more likely to have lower incomes (Table 1) and participants with higher income were more likely to consume herbal supplements (33% of participants with a higher than average monthly income were consumers in comparison with 21% of participants with an income of less than minimal wages, P = 0.009).
Table 1.
Baseline characteristics
| Consumer of herbals | Nonconsumer of herbals | |||
|---|---|---|---|---|
| 26.8% (n = 80) | 73.2% (n = 219) | P-value | 95% CI* | |
| Average age (years) | 63 ± 16 | 55 ± 16.5 | <0.001 | 4.4, 12.8 |
| Males | 51.3% (41) | 66.7% (146) | 0.021 | 2.8, 28 |
| Females | 48.8% (39) | 33.3% (73) | 0.021 | 2.9, 28 |
| Family status | 0.033 | |||
| Bachelor | 3.8% (3) | 11.9% (26) | 7.8, 8.4 | |
| Married | 72.5% (58) | 73.1% (160) | 10.8, 12 | |
| Divorcee | 5% (4) | 5.9% (13) | −4.8, 6.6 | |
| Widower | 18.8% (15) | 9.1% (20) | 8.8, 19.0 | |
| Children (average) | 2.35 ± 0.8 | 2.42 ± 0.9 | 0.546 | −0.28, 0.15 |
| Monthly income | 0.009 | |||
| Below minimal wages | 42.3% (22) | 48.2% (80) | −6.1, 17.9 | |
| Minimal to average wages | 21.2% (11) | 35.5% (59) | 3.4, 25.2 | |
| Slightly higher than average wages | 25.0% (13) | 9.0% (15) | 5.8, 26.2 | |
| Higher than average | 11.5% (6) | 7.2% (12) | 3.4, 12 | |
| Education | 0.006 | |||
| No school | 6.3% (5) | 5.5% (12) | 5.3, 6.9 | |
| Primary school | 28.8% (23) | 38.1% (83) | −2.5, 21.1 | |
| High school | 31.3% (25) | 40.8% (89) | −2.5, 21.5 | |
| Tertiary | 33.8% (27) | 15.5% (34) | 6.9, 29.7 | |
| Profession | 0.016 | |||
| Free profession | 38.2% (29) | 19.7% (40) | 6.7, 30.3 | |
| Blue collar workers | 40.8% (31) | 53.7% (109) | 0.1, 25.7 | |
| Sales, secretarial | 10.5% (8) | 15.3% (31) | −3.2, 12.8 | |
| Housewives | 10.5% (8) | 11.3% (23) | 0.1, 7.8 | |
| Smoking status | 0.005 | |||
| Nonsmoker | 57.5% (46) | 41.7% (91) | 3.2, 28.4 | |
| Past smoker | 28.8% (23) | 26.1% (57) | −14.2, 8.8 | |
| Current smoker | 13.8% (11) | 32.1% (70) | 8.6, 28 | |
| Alcohol consumption | 0.414 | |||
| Abstinence | 61.3% (49) | 66.4% (144) | −7.2, 17.4 | |
| Occasional | 38.8% (31) | 33.6% (73) | −17.5, 7.1 |
Confidence intervals are of difference of proportions. Confidence intervals of age and children are of difference of averages.
Education and profession were associated with supplement consumption. The higher the level of education the greater the tendency was to consume supplements: 33.8% of the HC vs. 15.5% of the NC were academics (P= 0.006). Of the patients with free professions, 42% consumed herbal supplements in comparison with 22–25% of patients with other professions. More of the consumers were free professionals and blue-collar workers in comparison with the NC (Table 1).
There was no difference in the alcohol consumption habits of the two groups, whereas smoking habits differed. There were fewer smokers in the HC group in comparison with the NC group (13.8 vs. 32.1%) (Table 1). Of the smokers, 13.6% consumed supplements vs. 33.6% of the nonsmokers and 28.8% of the past smokers (P= 0.005).
Herbal and dietary supplement consumption
Of the 299 participants, 80 (26.8%) consumed one or more herbal or dietary supplement for various indications as detailed in Table 2. Frequent indications were general wellbeing (28%) and constipation (18%). Thirty percent of the supplements were multivitamins, but an additional 48 different herbals were reported.
Table 2.
Indications for herbal remedies or dietary supplements
| Indication | Percent (n) |
|---|---|
| General well-being | 28 (27) |
| Constipation | 18 (18) |
| Urinary tract diseases | 7 (7) |
| Hypercholesterolaemia | 4 (4) |
| Ischaemic heart disease | 2 (2) |
| Menopause | 2 (2) |
| Mood | 1 (1) |
| Infectious diseases | 1 (1) |
| Other | 37 (36) |
| Total | 100 (98) |
Various people had recommended the herbal supplements to the patients, as detailed in Table 3. Only 66% of these ‘advisers’ had any knowledge of the patients' medical history or medications.
Table 3.
Advocates of herbal remedies or dietary supplements
| Advocate | Percent of herbal remedies or dietary supplements recommended |
|---|---|
| Doctor | 40 |
| Friend | 22 |
| Advertisement | 14 |
| Pharmacist | 10 |
| Naturopath | 6 |
| Salesman | 5 |
| Nurse | 3 |
Association between consumption of herbals or dietary supplements and medical diagnosis
Of the diseases identified as the principle cause of hospitalization, the only one with which herbal supplement consumption was associated was ischaemic heart disease (IHD). Of patients with IHD as their leading diagnosis, 19.3% consumed herbal supplements, in comparison with 31.1% of patients who had a history of IHD although it was not the leading diagnosis in the current hospitalization (P= 0.030).
When analysing all previous and current medical diagnoses, however, hypertension, thromboembolic disease, benign prostatic hypertrophy (BPH) and cholelithiasis were all associated with herbal supplement consumption (see Tables 4 and 5).
Table 4.
Diseases associated with herbal remedy or dietary supplement consumption
| Disease | Percent of consumers with disease (N) | Percent of nonconsumers with disease (N) | P-value | 95% CI of difference |
|---|---|---|---|---|
| Hypertension | 56.3 (45) | 42.9 (94) | 0.049 | 0.8, 26 |
| Thromboembolic disease | 3.8 (3) | 0 (0) | 0.019 | −7.9, 0.3 |
| Benign prostatic hypertrophy | 13.8 (11) | 4.6 (10) | 0.010 | 1.2, 17.2 |
| Cholelithiasis | 5 (4) | 0 (0) | 0.005 | 1, 9 |
Table 5.
Percent of herbal supplement consumers per disease
| Disease | Rate of patients with disease who consume herbal remedies or dietary supplements |
|---|---|
| Hypertension | 32.4% |
| Thromboembolic disease | 100% |
| Benign prostatic hypertrophy | 52.4% |
| Cholelithiasis | 100% |
There was no association between the consumption of herbal supplements and conventional medications.
Multivariate logistic regression analysis including baseline characteristics, medical history, principle diagnosis and medications was performed in order to discover the variates associated with herbal supplement consumption. The only variates so associated were: the hospital (Assaf Harofeh or Haemek), P = 0.01 [odds ratio (OR) 2.97, 95% confidence interval (CI) 1.29, 6.52]; income, P = 0.034 (OR 0.39, 95% CI 0.15, 1.05); smoking habits, P = 0.03 (OR 0.17, 95% CI 0.05, 0.55); and BPH, P = 0.18 (OR 4.64, 95% CI 1.3, 16.5).
The medical teams' and family doctors' awareness of herbal or dietary supplement consumption
Of the HC, 59% stated that their family doctor was aware of the supplement. For 44% of the HC it was the family doctor who recommended the supplement and 30% had informed the doctors themselves of the supplement consumption. Forty-one percent of the HC had not informed their family doctor, for reasons detailed in Table 6.
Table 6.
Reasons given for not informing the medical team and family doctor of herbal remedy and dietary supplementation
| Patient's explanation | Family doctor | Hospital medical team |
|---|---|---|
| Not important | 42% | 55% |
| Not medicine | 18% | 18% |
| The doctor doesn't understand | 18% | 3% |
| The doctor didn't ask | 15% | 24% |
| Plan to inform in the future | 6% | |
| Reluctant to insult the doctor | 0% | 0% |
The hospital medical team was aware of the herbal consumption of 28% of the HC. Ninety-four percent of the patients had not been asked specifically about herbal consumption by the medical team. The reasons the HC gave for not informing the medical team are detailed in Table 6.
Herbal consumption as evident from the medical records
Of the hospital medical files of the HC patients, 23% had some record of herbal supplement consumption. The hospitals were similar in this respect (P= 0.276); 13.7% of records had complete information, whereas 9.6% had partial records of herbal supplement consumption.
Drug–herbal interactions
A total of seven possible drug–herbal interactions were encountered (7.1%), as detailed in Table 7.
Table 7.
Drug–herbal interactions encountered
| Herbal supplement | Interacting drug | Type of interaction | Details |
|---|---|---|---|
| Calcium | Aspirin | Pharmacokinetic | Enhanced renal elimination of salicylates, due to urinary alkalinization |
| Calcium | Aspirin | Pharmacokinetic (elimination) | Enhanced renal elimination of salicylates, due to urinary alkalinization |
| Niacin | Simvastatin | Pharmacodynamic | Increased risk of myopathy and rhabdomyolysis |
| Biotin | Metformin | Pharmacodynamic | Hypoglycaemia. Biotin stimulates glucokinase, resulting in increased synthesis of glycogen, and also stimulates the secretion of insulin in the pancreas of rats, both glucose-lowering effects [16] |
| Midro tea | Famotidine | Pharmacokinetic (absorption) | Reduces absorption of famotidine |
| Cranberry | Famotidine | Pharmacodynamic | Antagonizes effect of famotidine by reducing gastric pH |
| Camomile tea | Ciclosporine (metabolism) | Pharmacokinetic | Camomile inhibits CYP3A4 and ciclosporin levels may rise |
Discussion
Complementary medical care in the western world has becoming increasingly common over the past few decades and, along with acupuncture, various massages and homeotherapy, the rate of consumption of herbal remedies is increasing [9] A growing number of patients consume herbal remedies with or without conventional medication [6]. Medical professionals are often not aware of the advantages or dangers of these remedies, including possible interactions that may be encountered with conventional medications [3–5].
The results of this study indicate that approximately one-quarter of patients hospitalized in a medical ward take herbal remedies or dietary supplements on a permanent basis, together with their other medications. More disturbing is that in 72% of the cases, the hospital medical team was unaware of this fact. In the cases the medical team was aware it was due to patients volunteering the information themselves; 94% of patients had never been asked specifically about their herbal remedy consumption. Patients, however, often did not volunteer the information, mostly because they did not consider the herbal remedy as important medical information, as they did not consider the remedy as a medication at all.
The family doctor patients' files were not reviewed, but taking into account the patients' judgement of the family doctors' awareness of herbal or supplement consumption, this study implies that family doctors had more knowledge of the consumption, and were often the advocates of the remedy.
The hospital medical teams' unawareness of the fact that approximately one-quarter of patients hospitalized in medical wards consume herbal remedies or dietary supplements made the chance of overlooking an important drug–herb interaction very large. The fact that the major diagnosis itself may be due to herbal adverse effects or herb–drug interactions may also be overlooked. We found no association between herbal remedy consumption and the major diagnosis (reason for hospitalization), other than an inverse relationship between IHD and herbal consumption. Fewer patients with IHD as their major diagnosis consumed herbal remedies in comparison with patients with IHD in their previous medical history. Herb–drug interactions may have caused exacerbation of chronic diseases leading to hospitalization, via herb–drug interactions, although this was beyond the scope of this study.
Knowledge of herb–drug interactions has been fast expanding in the past decade. Ginkgo biloba, for example, has been associated with bleeding, especially when combined with conventional antithrombotics or anticoagulants [10–14]. Ginseng, one of the best selling herbal medications in the USA, advocated to improve general health, combat fatigue and improve immune function [15], has serious interaction with warfarin, decreasing the anticoagulant effect, potentially endangering patients on chronic anticoagulant treatment [16]. St John's wort, used to treat depression, anxiety and nervous unrest [17], may also reduce the efficacy of drugs such as warfarin, simvastatin and theophylline, ciclosporin and oral contraceptives, presumably via induction of the cytochrome P450 glycoprotein 3A [18–21]. Echinacea, one of the most popular herbal remedies used for the treatment of the common cold, cough, bronchitis, influenza and pharyngitis, inhibits the activity of cytochrome P450 glycoprotein 1A2 and 2C9, which may result in toxic effects of drugs with a narrow therapeutic index such as theophylline, warfarin and phenytoin [22]. Digoxin toxicity has been associated with licorice-containing laxative [23] and Hawthorn leaf advocated for the treatment of mild heart failure [18].
We found a potential drug–herb interaction in 7% of the herbal consumers and in none of the cases was the medical team aware of the possibility and less than half of these cases had any record of herbal or dietary supplement consumption in the medical file.
The most significant drug–herbal interaction this study uncovered was a potential interaction between ciclosporin and camomile tea. The patient had had a renal transplantation 2 weeks prior to hospitalization and was currently hospitalized with a urinary tract infection. He had started drinking camomile tea a few days prior to hospitalization. His drug regimen consisted of ciclosporin and a number of other immunosuppressive drugs. Camomile tea could have caused ciclosporin toxicity via inhibition of CYP3A4. The patient's ciclosporin concentrations were not elevated but we recommended stopping the camomile tea. The medical team was unaware of the camomile tea and of the interaction with ciclosporin.
Multivariate analysis was able to determine a number of patient characteristics that may predict herbal consumption, such as hospital, higher income, past or nonsmokers and patients with BPH. The Assaf Harofeh Medical Centre had a higher rate of herbal consumers, due partially to the fact that the average income of the participants was higher, but possibly due to other factors that were beyond the scope of this study, such as ethnic differences, religious beliefs, accessibility of herbal remedies, etc. Past smokers or nonsmokers were more likely to be herbal consumers in comparison with current smokers, possibly due to the higher health awareness in this population, although this too was beyond the scope of the study to establish. BPH was the only disease associated with herbal remedy consumption. Our study was not large enough to establish an association between this condition and a specific herbal remedy, although most of the BPH patients were not taking herbal remedies to treat their prostate condition.
Income, smoking status and BPH, associated by multivariate analysis with herbal remedy consumption, are all nonspecific and common characteristics that indicate that the best method to discover these herbal consumers would be to ask all patients, just as would be done for medications in the regular medical interview. It would seem appropriate, in light of this study, to improve awareness of hospital medical teams to the importance of herbal remedies, due to drug–herbal interactions and herbal adverse effects and toxicity. The medical interview with a patient should always include information on herbal remedies of all types. Patients should also be made aware of the importance of herbal remedies and should be encouraged always to volunteer this information to medical teams. Patients should be aware of the potential of drug–herb interactions and should consult a medical professional before initiating a herbal remedy, as we found that approximately 40% of the advocates of the herbal therapy were unaware of the patients' medical conditions and medications.
Our study has a number of limitations. This was a convenience sample of patients, as not all of the patients hospitalized were interviewed. The number and characteristics of patients not interviewed were not recorded. Some could not participate due to their medical condition, so unfortunately this heterogenic subpopulation was under-represented in our study. This may have influenced the rate of herbal consumption, and possible drug–herb interactions could have been missed, but would probably not have changed the distressing results as to the medical teams' unawareness of the subject, and was therefore excluded from all analysis.
This study is also limited by the fact that the patients enrolled were all hospitalized in medical wards. Results may be different in other subgroups of patients such as surgical patients and possibly children.
An additional limitation is the fact that the patients were enrolled and interviewed by five different investigators with different qualifications (one medical doctor, three pharmacists and one nurse). All used a standardized questionnaire, which probably reduced the chance of variability, although this cannot definitely be ruled out.
In conclusion, herbal and dietary supplement consumption is common amongst patients hospitalized in internal medicine wards and is often overlooked by the medical team. Patients and doctors should be more aware of herbal adverse effects and herb–drug interactions.
Competing interests: None declared.
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