Abstract
Introduction
The study evaluated the recurrence of acute upper respiratory tract infections (aURTIs) and the number of antibiotic prescriptions within a 12-month follow-up period in patients prescribed with either homeopathic medicines or medicines from one of four conventional medication classes for aURTI therapy.
Methods
This explorative cohort study used real-world electronic healthcare data from the Disease Analyzer database (IQVIA). Included were patients of all ages from Germany with an index diagnosis of aURTI between 2010 and 2018, who had prescriptions for either homeopathic, conventional cough and cold, nasal, or throat medicines or nonopioid analgesics on the day of diagnosis or within 6 days afterwards. aURTI recurrence was assessed by multivariable logistic regression, the number of antibiotic prescriptions by multivariable negative binomial regression.
Results
From 3,628,295 patients with aURTI diagnosis initially identified in the database in the relevant time interval, a total of 610,118 patients, fulfilling the in- and not violating the exclusion criteria, were retained for analysis. In the multivariate analyses on all patients, prescriptions of nasal medicines were associated with a significant, slightly higher (OR: 1.18, CI: 1.10–1.26, p < 0.001) risk of aURTI recurrence compared to homeopathic medicines within 12 months. Prescriptions of cough and cold (OR: 0.92, CI: 0.86–0.97, statistically significant, p = 0.005) as well as throat medicines (OR: 0.93, CI: 0.86–1.01, p = 0.086) and nonopioid analgesics (OR: 0.95, CI: 0.89–1.02, p = 0.181) were associated with slightly lower risk of aURTI recurrence compared to homeopathic medicines. In the analysis of the age-dependent subgroups, there were some deviations from the overall population in terms of statistical significance; however, the directions of the effect estimates were unchanged. Almost all results of negative binomial regression analyses assessing differences in the frequency of antibiotic prescriptions during follow-up, both in all patients and in the age-dependent subgroups, were statistically significant in favor of homeopathic medicines.
Conclusion
The study demonstrated that follow-up recurrence and antibiotic prescriptions in patients with uncomplicated aURTI are at least comparable between patients treated with homeopathic and conventional medicines in real-world practice. Despite some methodological limitations inherent to the database used, the results of this study indicate that homeopathic medicines present a valuable therapeutic option for managing aURTI.
Keywords: Acute upper respiratory tract infections, Homeopathic medicines, Conventional medicines, Real-world data, Cohort study
Zusammenfassung
Einleitung
Die Studie untersuchte das Wiederauftreten von akuten Infektionen der oberen Atemwege (aURTI) und die Anzahl der Antibiotikaverordnungen innerhalb einer 12-monatigen Nachbeobachtungszeit bei Patienten, denen entweder homöopathische Arzneimittel oder Arzneimittel aus einer von vier konventionellen Arzneimittelklassen zur aURTI-Therapie verschrieben wurden.
Methoden
Für diese explorative Kohortenstudie wurden elektronische Gesundheitsdaten aus der Disease Analyzer Datenbank (IQVIA) verwendet. Eingeschlossen wurden Patienten aller Altersgruppen aus Deutschland mit einer aURTI-Indexdiagnose zwischen 2010 und 2018, denen am Tag der Diagnose oder innerhalb von sechs Tagen danach entweder homöopathische oder konventionelle Husten- bzw. Erkältungsmedikamente, Nasenmedikamente, Hals- bzw. Rachenmedikamente oder Nichtopioid-Analgetika verschrieben wurden. aURTI-Rezidive wurden mittels multivariabler logistischer Regression analysiert, die Anzahl der Antibiotika-Verschreibungen mittels multivariabler negativer Binomialregression.
Ergebnisse
Von den 3'628'295 Patienten mit einer aURTI-Diagnose, die im relevanten Zeitintervall ursprünglich in der Datenbank identifiziert wurden, konnten insgesamt 610'118 Patienten, die die Ein- und Ausschlusskriterien erfüllten bzw. nicht verletzten, in die Analyse einbezogen werden. In den multivariaten Analysen aller Patienten waren Verschreibungen von Arzneimitteln für nasale Symptome im Vergleich zu homöopathischen Medikamenten mit einem leicht erhöhten, statistisch signifikanten Risiko eines erneuten Auftretens einer aURTI innerhalb von 12 Monaten verbunden (OR: 1.18, KI: 1.10–1.26, p < 0.001). In den Gruppen mit Verschreibungen von Husten- und Erkältungsmitteln (OR: 0.92, CI: 0.86–0.97, statistisch signifikant, p = 0.005) sowie von Hals- und Rachenmitteln (OR: 0.93, CI: 0.86–1.01, p = 0.086) und Nichtopioid-Analgetika (OR: 0.95, CI: 0.89–1.02, p = 0.181) zeigte sich ein leicht geringeres Risiko für ein erneutes Auftreten einer aURTI im Vergleich zu homöopathischen Arzneimitteln. Zwischen den altersabhängigen Subgruppenanalysen gab es teilweise von der Gesamtpopulation abweichende Ergebnisse bezüglich der statistischen Signifikanz; die Richtungen der Effektschätzer waren jedoch unverändert. Fast alle Ergebnisse der negativen Binomialregressionsanalysen zur Bewertung von Unterschieden in der Häufigkeit von Antibiotikaverordnungen während der Nachbeobachtung waren in der Gesamtpopulation und in den altersabhängigen Subgruppen statistisch signifikant zugunsten homöopathischer Arzneimittel.
Schlussfolgerung
Die Studie hat im dargestellten Setting gezeigt, dass die Häufigkeit des Wiederauftretens der Erkrankung und die Verschreibung von Antibiotika in der Nachbeobachtungszeit bei Patienten mit unkomplizierter aURTI, die in der Praxis entweder mit homöopathischen oder konventionellen Arzneimitteln behandelt werden, weitgehend vergleichbar sind. Trotz einiger methodischer Einschränkungen im Zusammenhang mit der verwendeten Datenbank deuten die Ergebnisse dieser Studie darauf hin, dass homöopathische Arzneimittel eine wertvolle therapeutische Option für die Behandlung von aURTI darstellen.
Schlüsselwörter: Akute Infektionen der oberen Atemwege, Homöopathische Arzneimittel, Konventionelle Arzneimittel, Daten aus der Praxis, Kohortenstudie
Introduction
Acute upper respiratory tract infections (aURTIs) are benign diseases caused mainly by different virus families and rarely by bacteria. Signs of an aURTI are generally self-limiting and nonfatal symptoms such as sore throat, cough, rhinitis/rhinosinusitis, and malaise, which usually last 3–10 days. There are clear differences in the frequency of infections in the different age-groups, and they are particularly common in children up to 5 years of age [1–3]. An evaluation based on representative data from physician practices concluded that between April 2019 and March 2020, each general practitioner (GP) in Germany treated more than 500 patients with aURTI whereas this figure amounted to more than 1,500 by pediatricians [4]. Although aURTIs are mostly transient and mild diseases, they are economically highly relevant as they are one of the main reasons for productivity loss [2, 5].
Viral aURTIs cannot be causally treated with medication but at least symptoms can be relieved [6]. aURTI symptoms are predominantly self-medicated with over-the-counter medicines, including cough syrups, phytopharmaceuticals, nonsteroidal anti-inflammatory, analgesics, as well as homeopathic medicines. However, a significant proportion of patients with aURTI also receives a prescription for antibiotics, the use of which is inappropriate in many cases [7–9]. A current study from England reported that most antibiotic prescriptions for aURTI treatments occur within general practices [10].
Homeopathy is a therapeutic option that is used widely and in all age-groups [11]. The therapy uses both individually prescribed homeopathic medicines without fixed indication as well as homeopathic medicines with authorized indications, all available in a larger number of countries worldwide [12, 13]. Clinical studies (either randomized or non-randomized) of homeopathic medicines have shown effectiveness in a range of indications. Specifically, there have been several studies on the effectiveness of homeopathic medicines in treating aURTI [8, 11, 14, 15].
The most published results have been based on prospective clinical studies. However, there is still a need for real-world evidence on the use of homeopathic medicines and their potential treatment effects or impact on reducing and/or avoiding the use of conventional medicines. Real-world data (RWD) are an increasingly available and utilized source of clinical evidence. RWD cover among others registries, electronic health records, medical claims data, and prescription data and have increasingly been accepted by regulators, pharmaceutical companies, and patients during the last decades [16].
Studies utilizing RWD have also gained significance in assessing comparative effectiveness. This is particularly crucial because conducting head-to-head comparisons of single medicines or entire classes of medicines in the clinical trial setting is rare, time-consuming, and costly [17]. However, documented RWD related to homeopathy remain limited, especially for acute diseases [18].
This study is a step toward closing this knowledge gap by using RWD to compare homeopathic and conventional treatments in terms of aURTI recurrence and frequency of antibiotic prescriptions. These data also serve to corroborate the role of homeopathic treatment in the routine management of aURTIs. The analysis is based on a large pharmacoepidemiological database from a patient cohort in Germany.
Methods
Database
The present explorative study used data from the German Disease Analyzer database (IQVIA). This database has already been extensively described in the literature [19]. To summarize, the Disease Analyzer database includes anonymized patient data on demographic variables, diagnoses, and prescriptions obtained in general and specialized practices in Germany. Diagnoses are coded using the International Classification of Diseases-10th revision (ICD-10). As the database does not contain any specific clinical information about the diseases (e.g., degree of severity, symptoms present) beyond the current ICD-coded diagnosis at the time of prescription, no other detailed comparisons of patients and disease progression can be made. The quality of the data is assessed every month based on several criteria (completeness of information about sex and age, linkage between diagnoses and prescriptions). Practices contributing regularly to the database are selected according to the yearly statistics of the German Medical Association, which include information on physician’s age, specialty group, community size category, and German federal state. It has been shown in prior research that the Disease Analyzer database is representative of all practices in Germany [19]. In last years, several epidemiological studies on URTI using Disease Analyzer database were published [20–23].
Study Population
The study included patients with a first diagnosis of aURTI (ICD-10 codes J00-J04 [acute nasopharyngitis, sinusitis, pharyngitis, tonsillitis, laryngitis, and tracheitis] or J06 [acute upper respiratory infections of multiple and unspecified sites]) in the period between January 1, 2010, and December 31, 2018 (index date). This time frame was chosen to exclude the COVID-19 period that significantly changed the infection situation and routine medical care [24]. Included patients got prescriptions for either homeopathic, conventional cough and cold, nasal (topical/systemic), throat, or nonopioid analgesic medicines on the day of diagnosis or within 6 days afterward. Medicines were classified according to WHO Anatomical-Therapeutical-Chemical (WHO ATC, shown in Table 1) classes. Only patients with an “uncomplicated” aURTI, in the sense that they initially did not need an antibiotic, were included. This definition is consistently applied in the text whenever the term “aURTI” is used in relation to the study population. Follow-up data were collected for a period of 365 days after the index date as far as data were available for the respective patient.
Table 1.
Assignment of medicines relevant for the analyses to ATC classes (all ATC codes given as WHO ATC codes, adapted to the official German version)
| Group | ATC classes |
|---|---|
| Homeopathic medicines | V60A, N02BH, R01AH, R01BH, R02AH, R05CH, R05FH, R05XH |
| Cough and cold medicines | R05 excluding R05CH, R05FH, R05XH (all homeopathic medicines), R05GB (antibiotics), R05CP (phytotherapeutic medicines) |
| Nasal medicines (topical/systemic) | R01 excluding R01AH, R01BH (both homeopathic medicines), R01AC (antiallergens), R01AP, R01BP (both phytotherapeutic medicines) |
| Throat medicines | R02 excluding R02AH (homeopathic medicines), R02AB (antibiotics), R02AP (phytotherapeutic medicines) |
| Nonopioid analgesics (incl. NSAIDs relevant in aURTI therapy) | M01AE, N02B excluding N02BH (homeopathic medicines), N02BP (phytotherapeutic medicines) |
| Antibiotics | J01, R02AB, R05GB |
aURTI, acute upper respiratory tract infection; ATC, Anatomical Therapeutic Chemical; WHO, World Health Organization.
The following patient exclusion criteria were applied: prescriptions of medicines for aURTI complaints from more than one therapeutic class at index date, aURTI diagnosis within the 90 days prior to the index date, prescriptions for medicines from at least one of the study’s therapeutic classes within 90 days prior to the index date, prescription for an antibiotic in the 90 days before to 13 days after the index date, prescriptions for antineoplastic or immunomodulatory medicines in the days from 90 days before to 365 after the index date, unknown sex or age, patients whose practice did not deliver data continuously for a given patient for at least 3 months before to 12 months after the index date.
Study Outcome
The study compared the association of medication in aURTI with the risk of first aURTI recurrence (new diagnosis after index date), time to first aURTI recurrence, risk and number of antibiotic prescriptions, time to first antibiotic prescription. These outcomes were assessed as relative effects of each of the four investigated groups of conventional medicines versus the group of homeopathic medicines. Each patient was followed up for up to 365 days after the index date. The analysis period for the outcomes was 14–365 days after the index date.
Statistical Analyses
As the group of patients treated with homeopathic medicines is compared to defined conventional medicine classes, the homeopathy group is set as reference group in all analyses. The four conventional groups are referred to thereafter as “cough and cold,” “nasal,” “throat,” and “nonopioid analgesics” groups, respectively. Multivariable logistic regression was used to analyze the association between study therapies and the first aURTI recurrence. The data were adjusted for age-groups, sex, health insurance coverage, season of index date (quaterly intervals), and specialty of diagnosing/prescribing doctor (GP, ear-nose throat specialist [ENT specialist], pediatrician). The odds ratios (ORs) and their 95% confidence intervals (95% CI) were calculated between the reference and the analysis groups. A random effect for practice identifier (ID) was included in the model to control for possible associations between the likelihood of individual doctors having a greater or lesser inclination to choose homeopathic medicines in treating the aURTI and their likelihood to also diagnose recurrence. Since the patients were observed for a standardized period after index date, there was no need to adjust the results for differential patient follow-up.
The analysis of the mean number of antibiotic prescriptions during follow-up (i.e., between day 14 and day 365 after the index date) was generally similar to that of the recurrence of the first aURTI in terms of the variables used for adjustment. The main difference between the analyses of our two endpoints was the structure of the outcome variable. While the latter analysis (recurrence of any aURTI) addresses a binary variable (Y/N), the former analysis included the number of antibiotic prescriptions, which are rare events. Usually, a Poisson distribution is used as a model for rare events, and consequently a Poisson regression instead of a logistic regression would have been applied. But since the Poisson distribution assumes that the mean is equal to the variance (one-parameter distribution) and this assumption may have been violated, a negative binomial model was used instead. Again, a random effect for the practice ID was included in the model and no adjustment for the different observation time was required.
The time to occurrence of the first aURTI diagnosis after index date (“URTI recurrence”) and time to first antibiotic prescription during follow-up were further specified by multivariable Cox regression analyses adjusted as described above. Results of the Cox regression models were given as the hazard ratio (HR) between the reference and the analysis groups. A graphical presentation of the cumulative rates of patients with at least one URTI recurrence over follow-up time (days 14–365 after index) is also given to provide further insight into the time course of these events per group of medicines.
A nominal p value of <0.05 is considered statistically significant (in an exploratory sense); no adjustment for multiplicity was done. All analyses were carried using SAS version 9.4 and were based on a pre-established study protocol.
Results
Baseline Characteristics
Initially, a total of 3,628,295 patients with an aURTI diagnosis in the period between January 1, 2010, and December 31, 2018, were identified in the database. Overall, 610,118 patients (16.8%) were eligible for analyses (Fig. 1). Among those, 49,361 (8.1%) received prescriptions for homeopathic medicines. Female patients predominated in the homeopathic group (58.6%) and throat group (59.6%); in the other therapeutic groups, the sex ratio was more balanced. The proportion of privately insured patients was highest in the homeopathic (13.8%), moderately lower in the throat (11.8%) and nasal (11.5%) groups, and distinctly lower in the cough and cold (9.1%) and nonopioid analgesics (6.9%) groups. For each group, the highest proportion of index dates was observed in the winter months December–February (range: 29.4–38.7%). In all groups, the GPs had the largest share of patients except for nasal and throat medicines where the ENT specialists dominated. Among the total population analyzed, approximately one-third were children and adolescents (0–17 years, n = 242,094, 39.7%). This proportion was similar in the homeopathic group (n = 16,842, 34.1%) and in the cough and cold group (n = 47,674, 29.4%). In the nonopioid analgesics and nasal groups, the proportion of children and adolescents (n = 73,822, 44.9%, and n = 99,481, 50.9%, respectively) was roughly equal to that of the adult population (18–75+ years). In the throat group, the percentage of children and adolescents was markedly lower (n = 4,275, 11.1%) (Table 2).
Fig. 1.
Selection of overall study patients for comparison of the therapeutic medication groups according to in- and exclusion criteria. Respective percentage values are referring to the initial aURTI cohort. aURTI, acute upper respiratory infection.
Table 2.
Baseline characteristics of study patients
| Therapy class | Homeopathic medicines | Cough and cold medicines | Nasal medicines (topical/systemic) | Throat medicines | Nonopioid analgesics | Overall patients counts |
|---|---|---|---|---|---|---|
| N (%)a | N (%)a | N (%)a | N (%)a | N (%)a | N (%) | |
| Total patient counts | 49,361 (8.1) | 162,042 (26.6) | 195,619 (32.1) | 38,665 (6.3) | 164,431 (27.0) | 610,118 (100.0) |
| Index age class | ||||||
| 0–5 years | 7,742 (15.7) | 21,274 (13.1) | 68,828 (35.2) | 98 (0.3) | 38,304 (23.3) | 136,246 (22.3) |
| 6–11 years | 4,773 (9.7) | 14,048 (8.7) | 19,460 (9.9) | 968 (2.5) | 21,498 (13.1) | 60,747 (10.0) |
| 12–17 years | 4,327 (8.8) | 12,352 (7.6) | 11,193 (5.7) | 3,209 (8.3) | 14,020 (8.5) | 45,101 (7.4) |
| 0–17 years | 16,842 (34.1) | 47,674 (29.4) | 99,481 (50.9) | 4,275 (11.1) | 73,822 (44.9) | 242,094 (39.7) |
| 18–24 years | 5,666 (11.5) | 14,910 (9.2) | 13,301 (6.8) | 4,991 (12.9) | 17,456 (10.6) | 56,324 (9.2) |
| 25–49 years | 16,947 (34.3) | 50,960 (31.4) | 46,307 (23.7) | 14,971 (38.7) | 47,032 (28.6) | 17,6217 (28.9) |
| 50–74 years | 8,461 (17.1) | 38,705 (23.9) | 30,449 (15.6) | 11,254 (29.1) | 22,604 (13.7) | 111,473 (18.3) |
| ≥75 years | 1,445 (2.9) | 9,793 (6.0) | 6,081 (3.1) | 3,174 (8.2) | 3,517 (2.1) | 24,010 (3.9) |
| 18–75+ years | 32,519 (65.9) | 114,368 (70.6) | 96,138 (49.1) | 34,390 (88.9) | 90,609 (55.1) | 368,024 (60.3) |
| Patient sex | ||||||
| Male | 20,437 (41.4) | 76,409 (47.2) | 92,433 (47.3) | 15,625 (40.4) | 84,445 (51.4) | 289,349 (47.4) |
| Female | 28,924 (58.6) | 85,633 (52.8) | 103,186 (52.7) | 23,040 (59.6) | 79,986 (48.6) | 320,769 (52.6) |
| Patient health insurance | ||||||
| Statutory | 42,562 (86.2) | 147,299 (90.9) | 173,170 (88.5) | 34,112 (88.2) | 153,086 (93.1) | 550,229 (90.2) |
| Private | 6,799 (13.8) | 14,743 (9.1) | 22,449 (11.5) | 4,553 (11.8) | 11,345 (6.9) | 59,889 (9.8) |
| Season of index date | ||||||
| Months 12-2 | 16,238 (32.9) | 62,678 (38.7) | 62,395 (31.9) | 11,369 (29.4) | 57,648 (35.1) | 210,328 (34.5) |
| Months 3–5 | 12,156 (24.6) | 39,462 (24.4) | 48,768 (24.9) | 9,620 (24.9) | 39,077 (23.8) | 149,083 (24.4) |
| Months 6–8 | 7,822 (15.8) | 17,188 (10.6) | 28,582 (14.6) | 7,465 (19.3) | 25,338 (15.4) | 86,395 (14.2) |
| Months 9–11 | 13,145 (26.6) | 42,714 (26.4) | 55,874 (28.6) | 10,211 (26.4) | 42,368 (25.8) | 164,312 (26.9) |
| Doctor specialty | ||||||
| GP | 29,373 (59.5) | 113,526 (70.1) | 44,003 (22.5) | 18,007 (46.6) | 101,530 (61.7) | 306,439 (50.2) |
| Pediatrician | 7,466 (15.1) | 34,740 (21.4) | 75,160 (38.4) | 1,032 (2.7) | 53,177 (32.3) | 171,575 (28.1) |
| ENT specialist | 12,522 (25.4) | 13,776 (8.5) | 76,456 (39.1) | 19,626 (50.8) | 9,724 (5.9) | 132,104 (21.7) |
aIn the first data line, percentage is in relation to total population over all therapy classes. In all other lines of the “medicine columns,” percentages are in relation to the total population within a therapy class.
URTI Recurrence
At the end of the follow-up period (12 months after index date), the incidence rate of patients with at least one aURTI recurrence ranged from 16.1% to 29.3% (Table 3; Fig. 2). It was highest in the nasal group (29.3%), followed by the nonopioid analgesics group (26.7%). In the homeopathic and cough and cold group, the percentage of patients was lower, at comparable rates (23.1% and 22.9%). It was lowest in the throat group (16.1%). Results of multivariable logistic regression analyses, adjusted for any potential effects of the available covariates, showed that nasal medicine prescriptions were associated with a slightly higher risk of aURTI recurrence as compared to homeopathic medicines in the total population (OR: 1.18, 95% CI: 1.10–1.26) and in children and adolescents (OR: 1.27, 95% CI: 1.16–1.39), both statistically significant (p < 0.001 each). Prescription of cough and cold medicines showed a slightly lower risk of first aURTI recurrence as compared to homeopathic medicines in the total population (OR: 0.92, 95% CI: 0.86–0.97, p = 0.005), in adult patients (OR: 0.92, 95% CI: 0.86–0.98, p = 0.013), and in children and adolescents (OR: 0.92, 95% CI: 0.84–1.01, not statistically significant). Prescription of throat medicines showed a statistically significant lower risk in adult patients (OR: 0.87, 95% CI: 0.80–0.95, p = 0.002) (Table 3).
Table 3.
Results of the multivariable logistic regression of recurrence of the aURTIs in days 14–365 after index date
| Treatment | All patients | Children and adolescents | Adult patients | ||||||
|---|---|---|---|---|---|---|---|---|---|
| patients with event, % | OR (95% CI) | p value | patients with event, % | OR (95% CI) | p value | patients with event, % | OR (95% CI) | p value | |
| Homeopathic medicines | 23.1 | Reference | na | 29.5 | Reference | na | 19.8 | Reference | na |
| Cough and cold medicines | 22.9 | 0.92 (0.86–0.97) | 0.005 | 31.7 | 0.92 (0.84–1.01) | 0.092 | 19.2 | 0.92 (0.86–0.98) | 0.013 |
| Nasal medicines | 29.3 | 1.18 (1.10–1.26) | <0.001 | 41.0 | 1.27 (1.16–1.39) | <0.001 | 17.1 | 1.06 (0.99–1.15) | 0.109 |
| Nonopioid analgesics | 26.7 | 0.95 (0.89–1.02) | 0.181 | 33.6 | 0.96 (0.85–1.08) | 0.484 | 21.1 | 0.97 (0.90–1.04) | 0.365 |
| Throat medicines | 16.1 | 0.93 (0.86–1.01) | 0.086 | 22.4 | 1.08 (0.95–1.22) | 0.242 | 15.3 | 0.87 (0.80–0.95) | 0.002 |
Results were adjusted for age-groups, sex, patient health insurance coverage, season of index date, and specialty of diagnosing/prescribing doctor.
aURTI, acute upper respiratory tract infection; CI, confidence interval; OR, odds ratio; na, not applicable.
Fig. 2.
Graphical presentation of the cumulative incidence of first aURTI recurrence in days 14–365 after index date (log-rank test p < 0.001).
In multivariable Cox regression analyses of the time to a first aURTI recurrence adjusted for the mentioned set of covariates, the prescription of cough and cold medicines (HR: 0.93, 95% CI: 0.91–0.95), nonopioid analgesics (HR: 0.97, 95% CI: 0.95–0.99), and throat medicines (HR: 0.94, 95% CI: 0.91–0.97) were associated with slightly lower time-related risk of aURTI recurrence as compared to homeopathic medicines. Nasal medicines (HR: 1.16, 95% CI: 1.13–1.18) were associated with a higher time-related risk of aURTI recurrence compared to homeopathic medicines. All these results were statistically significant for the total population (p < 0.001). The directions of the point estimates of the HRs in both children and adolescents and adult patients were mostly similar but not in all cases statistically significant (Table 4). Time-related risks of first recurrence of aURTI within 1 year after initial aURTI diagnosis are similar in all studied therapeutic classes (Fig. 2). The cumulative proportion of all patients with a first recurrent aURTI over follow-up time also exhibits a similar pattern across all treatment groups, demonstrating a smooth and largely parallel consistent increase of those events despite differing maximum proportions at almost all timepoints, with most of these events occurring in the first 6 months of follow-up. As expected, this descriptive figure (Fig. 2) presenting the unadjusted data shows some differences to the adjusted results of the multivariate analyses of the time to first recurrence (Table 4).
Table 4.
Results of the multivariable Cox regression of time to 1st recurrence of the aURTIs in days 14–365 after index date
| Treatment | All patients | Children and adolescents | Adult patients | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |
| Homeopathic medicines | Reference | na | Reference | na | Reference | na |
| Cough and cold medicines | 0.93 (0.91–0.95) | <0.001 | 0.94 (0.91–0.97) | <0.001 | 0.93 (0.90–0.95) | <0.001 |
| Nasal medicines | 1.16 (1.13–1.18) | <0.001 | 1.22 (1.18–1.25) | <0.001 | 1.06 (1.03–1.09) | <0.001 |
| Nonopioid analgesics | 0.97 (0.95–0.99) | <0.001 | 0.98 (0.95–1.01) | 0.134 | 0.97 (0.95–1.00) | 0.075 |
| Throat medicines | 0.94 (0.91–0.97) | <0.001 | 1.07 (1.00–1.15) | 0.059 | 0.89 (0.85–0.92) | <0.001 |
Results were adjusted for age-groups, sex, patient health insurance coverage, season of index date, and specialty of diagnosing/prescribing doctor.
aURTI, acute upper respiratory tract infection; CI, confidence interval; HR, hazard ratio; na, not applicable.
Antibiotic Prescriptions
Multivariate negative binomial regression analyses showed lower mean numbers of antibiotic prescriptions in patients in the homeopathy group (total population as well as children and adolescents) compared to patients in the cough and cold and nasal groups, both statistically significant. In adult patients, this number was lower in the homeopathy group compared to the nonopioid analgesics group but higher compared to the nasal group (statistically significant) (Table 5).
Table 5.
Results of the multivariable negative binomial regression of the number of antibiotic prescriptions in days 14–365 after index date
| Treatment | All patients | Children and adolescents | Adult patients | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| total number of AB prescriptions | mean number of AB prescription per patient (SD) | means ratio (95% CI) | p value | total number of AB prescriptions | mean number of AB prescription per patient (SD) | means ratio (95% CI) | p value | total number of AB prescriptions | mean number of AB prescription per patient (SD) | means ratio (95% CI) | p value | |
| Homeopathic medicines | 9,312 | 0.19 (0.56) | Reference | na | 3,522 | 0.21 (0.60) | Reference | na | 5,790 | 0.18 (0.54) | Reference | na |
| Cough and cold medicines | 36,845 | 0.23 (0.61) | 1.09 (1.01–1.17) | 0.026 | 12,743 | 0.27 (0.68) | 1.19 (1.03–1.37) | 0.018 | 24,102 | 0.21 (0.58) | 1.05 (0.98–1.12) | 0.207 |
| Nasal medicines | 41,602 | 0.21 (0.61) | 1.14 (1.05–1.24) | 0.002 | 27,897 | 0.28 (0.72) | 1.18 (1.02–1.38) | 0.028 | 13,705 | 0.14 (0.48) | 1.10 (1.02–1.19) | 0.020 |
| Nonopioid analgesics | 38,221 | 0.23 (0.62) | 1.08 (0.99–1.16) | 0.069 | 17,688 | 0.24 (0.65) | 1.04 (0.89–1.20) | 0.640 | 20,533 | 0.23 (0.60) | 1.13 (1.05–1.22) | 0.001 |
| Throat medicines | 5,577 | 0.14 (0.48) | 0.96 (0.88–1.06) | 0.442 | 818 | 0.19 (0.56) | 1.17 (0.98–1.39) | 0.082 | 4,759 | 0.14 (0.47) | 0.93 (0.85–1.02) | 0.119 |
Results of the means ratios are adjusted for age-groups, sex, patient health insurance coverage, season of index date, and specialty of diagnosing/prescribing doctor. The p values provided are referring to the estimated means ratios, respectively.
AB, antibiotic; CI, confidence interval; SD, standard deviation; na, not applicable.
The overall number of antibiotic prescriptions during follow-up was low in all groups and 83.5–89.2% of patients did not receive any antibiotic prescription (Table 6). Overall, 8.2–11.9% of patients received one; 1.8–3.2% of patients received two antibiotic prescriptions (data not shown). Table 6 additionally shows the results of multivariable Cox regression analysis for the time to first antibiotic prescription. In the total population, homeopathic medicines were associated with lower time-related risk of antibiotic prescriptions when compared to cough and cold (HR: 1.10, 95% CI: 1.07–1.13), nasal medicines (HR: 1.14, 95% CI: 1.11–1.17), and nonopioid analgesics (HR: 1:08, 95% CI: 1.05–1.10) (all three statistically significant, p < 0.001). The HR of throat medicines as compared to homeopathic medicines was not statistically significant. Similar effects were observed in adult patients. In children and adolescents, homeopathic medicines were associated with statistically significant lower risk of antibiotic prescription when compared to cough and cold (HR: 1.19, 95% CI: 1.13–1.24, p < 0.001), nasal (HR: 1.18, 95% CI: 1.13–1.23, p < 0.001), and throat medicines (HR = 1.14, 95% CI: 1.04–1.25, p = 0.006).
Table 6.
Results of the multivariable Cox regression of time to 1st antibiotic prescription in days 14–365 after index
| Treatment | All patients | Children and adolescents | Adult patients | ||||||
|---|---|---|---|---|---|---|---|---|---|
| with AB, % | HR (95% CI) | p value | with AB, % | HR (95% CI) | p value | with AB, % | HR (95% CI) | p value | |
| Homeopathic medicines | 13.7 | Reference | na | 14.8 | Reference | na | 13.1 | Reference | na |
| Cough and cold medicines | 16.3 | 1.10 (1.07–1.13) | <0.001 | 18.3 | 1.19 (1.13–1.24) | <0.001 | 15.5 | 1.06 (1.03–1.10) | <0.001 |
| Nasal medicines | 14.8 | 1.14 (1.11–1.17) | <0.001 | 18.8 | 1.18 (1.13–1.23) | <0.001 | 10.7 | 1.10 (1.06–1.15) | <0.001 |
| Nonopioid analgesics | 16.5 | 1.08 (1.05–1.10) | <0.001 | 16.5 | 1.03 (0.98–1.07) | 0.222 | 16.4 | 1.14 (1.10–1.18) | <0.001 |
| Throat medicines | 10.8 | 0.98 (0.94–1.02) | 0.296 | 13.7 | 1.14 (1.04–1.25) | 0.006 | 10.4 | 0.96 (0.91–1.00) | 0.053 |
Results were adjusted for age-groups, sex, patient health insurance coverage, season of index date, and specialty of diagnosing/prescribing doctor.
AB, antibiotic prescription; CI, confidence interval; HR, hazard ratio; na, not applicable.
Discussion
The results of the present real-world cohort study including more than 610,000 patients with aURTI indicate that homeopathic and conventional medicines yield comparable outcomes when managing uncomplicated aURTI (i.e., without prescription of any antibiotic medication at or around index diagnosis as defined in the Methods section). Time-related risk of first recurrence of aURTI within 1 year after initial aURTI diagnosis is similar in all studied therapeutic classes.
Analysis of the time-related risk for first antibiotic prescription during follow-up revealed a slight, but significantly lower risk for patients in the homeopathic group compared to those in the cough and cold, nasal, and nonopioid groups. Considering the generally low frequency of antibiotic prescriptions during follow-up observed in this study, this finding is even more noteworthy. Patients who received throat medicines had a slightly reduced time-related risk for the first antibiotic prescription as compared to homeopathic medicines (not statistically significant). One possible explanation may be the partially bacteriostatic effect of a local treatment [25, 26].
In the past, clinical trials and prospective observational studies have already investigated patients with URTI treated with homeopathic medicines. For example, Zanasi et al. [27] conducted a randomized, double-blind, placebo-controlled clinical trial including 40 patients with URTI treated with a homeopathic syrup and 40 patients who received placebo. After 4 and 7 days of therapy, cough severity was significantly lower in the homeopathic group. Furthermore, sputum viscosity was significantly lower in the homeopathic group. Authors concluded that the homeopathic syrup might be a valid medication for URTI-induced acute cough.
In an open, randomized, controlled clinical study, Thinesse-Mallwitz et al. [28] analyzed the impact of a 7-day therapy with a homeopathic combination product given additionally to on-demand symptomatic standard treatment in pediatric and adult patients presenting with clinical signs and symptoms of an acute, feverish URTI. Therapy response was measured on treatment day 4 as absence of fever and absence or very mild degree of URTI symptoms. A total of 523 patients from Ukraine and Germany were included (258 receiving only standard medication, 265 receiving standard medication plus homeopathy). Response rate on day 4 was 6.7% in the group receiving only standard therapy and 15.4% in the group receiving additionally homeopathy. The latter group additionally used less symptomatic medication and symptoms were relieved 1–2 days earlier as compared with the former group. All these differences were significantly in favor of the group receiving additionally homeopathy.
Haidvogl et al. [8] reported the findings of an international multicenter, comparative cohort study on 1,577 children with URTI treated in 57 primary care practices. In their study, homeopathic treatment was shown noninferior to conventional treatment, and authors observed slightly faster onset of improvement with homeopathy than with conventional treatment.
Findings based on retrospective RWD from Disease Analyzer database (IQVIA) cannot be directly compared to results of such prospective clinical studies due to disparities in settings and availability of several variables. In contrast to the clinical studies that yield data with higher internal validity due to their controlled conditions, RWD provide more comprehensive insights into everyday clinical practices and thus potentially higher external validity. In the context of our study, they improve the understanding of the pharmacoepidemiologic patterns associated with the treatment of aURTIs in Germany and are thus a relevant aspect of health services research for this indication. Our results, for example, show that in real-world practice, two thirds of all patients who are otherwise eligible for our study are getting prescriptions of more than a single medication class and must be therefore excluded from the study.
As expected, the winter months (December–February) exhibit the highest occurrence of URTIs, followed by the autumn months (September–November). During the summer months (June–August), the incidence of URTIs is approximately 60% lower compared to the winter months. Our analysis also shows that around half of the patients seek treatment for their URTIs from GPs. Interestingly, this proportion is even higher for patients solely using homeopathic, cough and cold, or nonopioid analgesic medicines. In contrast, locally acting medications, like nasal and throat preparations, are prescribed mostly by ENT doctors. This, too, is not surprising as these medicines act specifically on the ENT symptoms. In the homeopathic group, almost 60% of patients are female and the proportion of patients having a private health insurance is slightly higher compared to the other therapy groups. This reflects characteristics that are frequently found among users of homeopathic medicines in Europe [29].
High-quality RWD can complement clinical studies by providing data on the effectiveness and safety of medicines with greater external validity supporting future regulatory [30] and clinical decisions. For example, current medical guidelines [31–33] are cautious in recommending symptomatic treatment of self-limiting aURTI diseases, but patients often request medicines to alleviate their complaints. In the light of our results, it is worth emphasizing the key advantages of homeopathic medicines, namely, the lower incidence and severity of side effects as well as a reduced number of contraindications compared to standard care [7, 9, 34]. These benefits make homeopathic medicines particularly valuable for vulnerable patients like children, the elderly, or persons under polypharmacy [35]. In the case of URTI, this is especially relevant when considering the side effects of some conventional medicines, like gastrointestinal bleeding for ibuprofen (nonopioid analgesics), drowsiness, dizziness, nausea, and vomiting for dextromethorphan (cough and cold), or dryness in the nose for phenylephrine (nasal), just to name a few [7].
Prescriptions of homeopathic medicines for aURTI are found to be potentially associated with reduced use of antibiotics. Grimaldi-Bensouda et al. [15] conducted the EPI3 cohort study in France, a population-based survey of 518 patients with acute URTI. Compared to patients treated by GPs who exclusively prescribe conventional medicines, patients treated by certified homeopathic GPs showed overall significantly lower consumption of antibiotics and antipyretic/anti-inflammatory drugs with similar resolution in URTI-related symptoms.
It is widely described in the literature that an inappropriate overuse of antibiotics in outpatient settings is a significant factor driving the rise of bacterial drug resistance. This issue is recognized as a major public health concern. In Germany, e.g., the analysis of almost 1.5 million patients diagnosed with at least one acute lower and/or upper respiratory tract infection between January 2015 and March 2019 showed that the overall prevalence of antibiotic prescription was 31% for patients treated by GPs and 9% in a similar group treated by pediatricians [36]. A cross-sectional national study conducted in France between 2015 and 2017 examined 221,768 pediatric visits [37]. The study revealed that respiratory tract infections account for over 80% of antibiotic prescriptions. Among these, presumed viral respiratory infections constitute 40.8% of antibiotic prescriptions by GPs and 23.6% by pediatricians.
Further reduction of antibiotic prescriptions, often even made for “prophylactic” purposes, is therefore urgently needed and has partly been reached in the last years. As example, in Finland, antibiotic prescriptions for uncomplicated URTIs decreased substantially between 2014 and 2020; however, 9% of children still received unnecessary antibiotics [38].
Considering the risks associated with antibiotics, such as the development of antimicrobial resistance and adverse drug reactions, it is essential to investigate alternative approaches for minimizing unnecessary antibiotic prescriptions [39]. Several clinical trials suggest overall comparable effectiveness of homeopathic and conventional treatment for URTI [9]. Our study compared these therapy options in daily practice and showed mostly comparable results regarding aURTI recurrence and antibiotic prescriptions in the follow-up period. Concerning aURTI recurrence, the results show rather small impact of the different therapeutic classes and investigated age-groups (total, children and adolescents, adult). In contrast, regarding antibiotic prescriptions the overall results are almost homogenously in favor of the homeopathic group compared to the other groups. Our results therefore propose that all investigated regimes could be likewise supportive in symptomatic treatment when applying a watchful waiting strategy [7]. According to medical guidelines [31–33], symptomatic treatment instead of antibiotic prescriptions is to be preferred for uncomplicated (no “red flags”) aURTIs.
Strengths and Limitations
To the best of our knowledge, this is the first RWD cohort study on aURTI in Germany comparing conventional to homeopathic medicines. Even if it can be compared to some extent to the EPI3-RWD survey on GP-treated patients in France in terms of diagnosis, our study includes a significantly higher number of patients [15]. This large patient sample (>610,000 patients), including children, adolescents, and adults, as well as the inclusion of three different medical specialist groups (GP, ENT, pediatricians), is clearly one of the strengths of this study. In addition, our research uses a prescription-based database, whose reliability and representativeness have been demonstrated in several studies, which supports the validity of the findings. Our study marks an important stride in bridging the information gap regarding RWD on the use of homeopathic medicines, more specifically in the context of treating aURTIs in everyday clinical practice.
Retrospective primary care database analyses are generally limited by the validity and completeness of data and the limitations mentioned below illustrate the difficulties in studies with nonprescription medicines using secondary data. One results from the fact that the primary prescribed medicines analyzed are, in principle, over-the-counter drugs. Nevertheless, a physician can issue a prescription if necessary. Regarding our study, this means that information on medicines used without prescription is missing in the database. Even if a medicine is prescribed by a physician, there is in this setting no confirmation that patients take it at all and in which quantity. Also, the database does not contain information on the severity grade of aURTI, or information on typical clinical outcome parameters, such as symptom duration and severity during follow-up or on quality of life. Therefore, the chosen criteria, aURTI recurrence and prescription of antibiotics for aURTI during follow-up, are a bridging approach to assess treatment outcomes in the given setting. Data on socioeconomic status and lifestyle-related risk factors (smoking, alcohol, physical activity) are also not available, and the possibility of residual confounding by these and other factors cannot be excluded. Moreover, the observation of patients is limited to a single practice each. Therefore, any diagnoses or prescriptions patients may have got from other doctors are not recorded. Considering that most patients take medicines from more than a single therapeutic class to manage their aURTI in daily practice, the dataset we analyzed cannot be considered representative for the totality of patients with aURTI in Germany. However, the allocation of patients into single therapeutic classes (i.e., excluding combinations of different classes) had methodological reasons. This design was chosen to facilitate the interpretation of the results in relationship to distinct therapeutic paths.
Conclusions
The present study contributes to comparative, real-world evidence on the use of homeopathic and conventional medicines in the treatment of children, adolescents, and adults with aURTI. It is a step toward closing the RWD knowledge gap on homeopathy. Despite some inherent methodological limitations of the database used, the results of this study of more than 610,000 patients suggest that homeopathic medicines are a valuable therapeutic option for the treatment of aURTI in primary care. Their good tolerability as reported in the literature and the fact that they can help to reduce the unnecessary use of antibiotics in patients with aURTI should also be considered within the wider context of healthcare decision-making. Further research utilizing different study designs and databases is needed to expand the real-world evidence for homeopathy.
Acknowledgments
The authors thank Dr. Karel Kostev and colleagues from IQVIA (Frankfurt, Germany) for numerous methodological discussions related to the analysis of the presented study data.
Statement of Ethics
Ethical approval was not required for this study in accordance with local/national guidelines. German law permits the utilization of anonymous electronic medical records for research, subject to specific conditions. Under this legislation, obtaining informed consent from patients or approval from a medical Ethics Committee is not obligatory for observational studies lacking directly identifiable data. As patients’ data were used in aggregated form only and no personal health data are reported at all, ethical approval was not mandated for utilizing the Disease Analyzer database (IQVIA) or conducting the study.
Conflict of Interest Statement
N.B. has received a fee from Deutsche Homöopathie-Union for providing advice during preparation of the manuscript. S.D.J. and S.N. are employees of Deutsche Homöopathie-Union. T.R. is employee of Dr. Willmar Schwabe GmbH & Co. KG.
Funding Sources
The analysis of the available data from Disease Analyzer database by IQVIA was commissioned and funded by Deutsche Homöopathie-Union (DHU-Arzneimittel GmbH & Co. KG, 76227 Karlsruhe, Germany).
Author Contributions
All authors contributed to the design of the study and drafted, corrected, revised, and approved the manuscript. N.B. and T.R. additionally defined the statistical analyses and presentation of the results.
Funding Statement
The analysis of the available data from Disease Analyzer database by IQVIA was commissioned and funded by Deutsche Homöopathie-Union (DHU-Arzneimittel GmbH & Co. KG, 76227 Karlsruhe, Germany).
Data Availability Statement
The Disease Analyzer database is property of IQVIA and not publicly available.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The Disease Analyzer database is property of IQVIA and not publicly available.