Conventional medicines versus homeopathy: the EPI3 Study

Conventional medicines versus homeopathy: the EPI3 Study Bernard Bégaud, MD, PhD Université Bordeaux Segalen, INSERM U657 Bordeaux, France

Disclosure The EPI3 Study was entirely funded by the Laboratoires Boiron (France) and conducted by the Contract Research Organization LA- SER Int. (Prof. Lucien Abenhaim Director). I acted as the Chair of the Scientific Advisory Board of the EPI3 Study at the request of Prof. Lucien Abenhaim (LA-SER). I (and I did not) have any financial link or contract (research or other) with Laboratoires Boiron. I currently chair a research unit in pharmacoepidemiology (INSERM U657) working without any support from the pharmaceutical industry.

Does my study told me the truth Experimental design Conditions are artificial Conclusions are robust Measures the intrinsic effect (efficacy) of the drug Observational design Based upon real life Conclusions may be affected by biases Measures the result of interactions between drug(s) and many factors present in real life.?

Experimental vs observational Randomization Robustness Not representative Small samples Standardized Criteria: robust but not realistic Prescription Prone to biases Representative Large populations Real life Criteria: pragmatic

Controlling for confounding Experimental designs (clinical trials): protected from biases by randomisation Observational designs Matching Stratification Adjustment (e.g. logistic model)

Molecule Cells Rats Human (Phases I to III) Populations Drugs are developed in order to increase health and welfare of individuals and populations, not only to induce publishable effects in rats nor to win a cup in a clinical trial contest!

The golden rule of assessment The results of an experiment are generalizable if, and only if, the conditions of this experiment have not been altered.

Comparing homeopathic to conventional medicines Hard choice: Experimental: Robust but often not feasible Observational: Feasible but often questionable

Comparing homeopathic to conventional medicines The choice depends upon the purpose of the assessment: To compare a homeopathic remedy with a conventional medicine? experimental design To compare 2 practices in a public health perspective? observational design.

The EPI 3 Programme (1) Funded by Laboratoires Boiron Design, coordination, analyses: Pr Lucien Abenhaim and staff (LA-SER, Paris, London) Scientific Advisory Board (chair: Pr Bernard Bégaud, Bordeaux) Conducted: March 2007 to July 2008 Country: France.

EPI 3 Programme (2) Observational Field Actual practice, real life Patients recruited in consulting rooms Combining cross-sectional (descriptive) and cohort approaches (explicative).

EPI 3 Programme (3). Cross-sectional study (1) Random sample of French community practitioners (850 finally included): Allopaths: 196 Homeopaths: 256 Mixed practice: 352 Patients recruited in consulting rooms, during one random day of practice No more than 15 patients/practitioner

EPI 3 Programme (4). Cross-sectional study (2) 11809 patients identified in consulting rooms (one random day) 8652 (73.3%) accepted to participate 6359 (53.8%) accepted and fulfilled the inclusion criteria: 1501 for homeopathic practice 1691 for allopathic practice 3187 for mixed practice.

EPI 3 Programme (5). Cross-sectional study (3) To describe patients and symptoms and diseases actually seen in general practice: Patients characteristics urden of diseases Comparing practices and prescriptions of physicians (e.g. 20% of «allopaths» daily prescribed homeopathy what accounts for 40% of homeopathy remedies prescribed in France).

Distribution of diseases according to practice Fréquences en ordonné, en abscisse : A : Maladies de l'appareil respiratoire et ORL-O, B : Maladies du système musculo-squelettique, C : Troubles névrotiques et troubles du sommeil, D : Maladies cardiovasculaires et du métabolisme, E : Maladies endocriniennes, F : Maladies de l'appareil digestif, G :Maladies des organes génitourinaires, H : Maladies du système nerveux, tête et cou, I : Maladies de la peau et du tissu sous-cutané, J : Maladies infectieuses et parasitaires systémiques, K : Lésions traumatiques et empoisonnements, L : Grossesse, post-partum, nouveau-né, enfant, M : Motifs de recours aux services de santé (motifs administratifs et préventifs, vaccinations, bilans biologiques et radiologiques, symptomes généraux ), N : Autres maladies (cancer et maladies peu communes)

Characteristics of physicians according to practice Allopaths Mixed Homéopaths N=196 N=352 N=256 Age (year) median (Q1-Q3) 52 (45-57) 50 (45-56) 52 (47-56) Frequency (%) Female 20,4 31,0 48,8 Practicing alone (%) 51,5 56,0 73,1 Salaried 34,5 16,9 14,3 Type of contract with reimbursement system - Type 1 92,3 90,6 41,8 - Type 2 7,7 6,0 50,4 - None 0 1,1 6,3 Use of non-conventional therapies (daily or often) Acupuncture 2,0 9,9 34,0 Mesotherapy 7,7 20,4 16,0 Phytotherapy 7,7 41,5 53,1 Other 9,2 10,2 31,6 Having prescribing homeopathy the study day (%) No 92,4 67,1 6,3 Once 5,6 15,4 5,1 Twice and over 1,0 17,5 88,6

Characteristics of patients Patients referring to homeopathy practice were: More often women (69.5% vs 57.4%) Mainly 40 to 59 years With a higher education level More often with BMI < 25 Less often smokers In better health condition Presenting more often with affective disorders.

EPI 3 Programme (5) Cohort studies Three cohorts including patients (n = 4899) who presented with: SAD (sleep disorders, anxiety, depression) : 1350 patients included DMS (rheumatology): 1905 patients included IVAS (upper respiratory tract infections) : 1644 patients included Follow-up: 3 days, 1 month, 3 months and 1 year Interviews made by the LA-SER team Scales and questionaires: SF12, MCS, PCS, CAMBI, and: SAD: HAD for anxiety and depression, Berlin CRF and Pittsburg for sleep disorders. DMS: Eifel, Lequesne, Quickdash IVAS: clinical assessment (structured questionnaire)

Controlling for putative biases Adjustment (logistic model) on: Age Sex Education level Number of consultations during the 12 preceding months Number of hospitalisations in the past Physical activity Comorbidity Factors specific to the disease considered (SAD, DMS, IVAS).

Improvement of anxiety and depression (HAD<9) Follow-up Allopaths Homéopaths Mixed practice 1 month 8.5% 16.1% 11.6% 3 months 10.4% 22.0% 15.7% 12 months 13.9% 18.5% 22.5%

Probabilty of recovering (SAD) OR* (IC 95%) 3,6 3,4 3,2 3 2,8 2,6 2,4 2,2 2 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 Tout médecin Médecin traitant 1,8 1,62 1,62 1 1 1,92 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, PCS, antécédent de TS, sévérité du trouble, traitement prévalent

Recovery of sleep disorders Allopaths Homéopaths Mixed 1 month 30.6% 34.1% 38.6% 3 months 51.6% 37.9% 45.5%

Psychotropic users Follow-up Allopaths Homeopaths Mixed practice 1 month 86.0% 45.2% 69.8% 3 months 74.4% 46.0% 62.8% 12 months 68.0% 46.5% 63.5%

Use of psychotropics by SAD patients SAD patients ++ Allo (%) Mixed Homeo Antidepressants 69.9 59.0 0.58 (0.42 0.80) 35.3 0.23 (0.16 0.33) Anxiolytics and hypnotics 51.4 54.2 1.15 (0.84 1.57) 31.3 0.44 (0.31 0.63) Antipsychotics 4.0 5.2 1.22 (0.58 2.58) 4.0 1.18 (0.50 2.81) Normothymics 5.5 1.4 0.24 (0.10 0.60) 4.7 0.91 (0.42 1.99) Homeopathy for Mood disorders 0-7.8 0.10 (0.07 0.16) 43.7 Ref. * From polytomic regressions adjusted for, employment status (unemployed, retired vs. employed), age ([39-59[, 60+ vs. [18-39[), education level (high school deg ** plus adjusted for severity of anxiety (HAD score >12 versus below) + plus adjusted for severity of depression (HAD score >12 versus below) ++ plus adjusted for both severity of anxiety and depression (HAD score >12 versus below)

Probability of using a psychotropic drug during follow-up (SAD) 1,2 Tout médecin Médecin traitant 1 1 1 0,8 OR* (IC 95%) 0,6 0,4 0,62 0,41 0,64 0,36 0,2 0 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, PCS, antécédent de TS, sévérité du trouble, traitement prévalent

1,6 1,4 Probability of fall during follow-up (SAD) Tout médecin Médecin traitant 1,2 OR* (IC 95%) 1 0,8 0,6 0,4 1 0,46 0,65 1 0,4 0,55 0,2 0 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, PCS, antécédent de TS, sévérité du trouble, traitement prévalent

Temporal trends of the DMS scales* over 12 months According to type of practice (N=1153) Mixed (AH) Allopaths Homéopaths * Tests statistiques par ANCOVA pour mesures répétées ajustés pour sexe, âge, valeur du score à 72hrs, Chronicité à l inclusion et score de propension. Tous les deltas de temps sont significatifs (p<0.001) sauf différences 3M 12M. Pas de différence significative entre les types de médecins (p >0.5).

Number of antiinflammatory and analgesic drugs used by DMS patients during follow-up Number of drugs declared per 100 patients (95% confidence interval) 2 Allo Mixed Homeo Non-Chronic DMS Chronic DMS NSAIDs 102.4 78.7-126.1 120.5 95.4 145.6 63.1* 32.5 93.7 Analgesics 309.7 265.8-353.5 385.2* 351.8-418.6 256.4 209.4 303.4 NSAIDs 117.6 89.6-145.6 113.7 91.3 136.1 59.0* 34.5 83.5 Analgesics 335.2 292.9 377.5 357.0 322.0-392 250.5* 211.5 289.5 Physicians prescription preferences: CM = conventional medicine; Mx = mixed practice, conventional and CAMs; Ho = registered homeopathic Number of different drugs consumed over twelve months declared by 100 patients; means adjusted for propensity score. * Comparison with CM category: p<0.05.

Probability of recovering (IVAS) 1,8 1,6 Tout médecin Médecin traitant 1,4 1,2 OR* (IC 95%) 1 0,8 0,6 1 0,71 0,92 1 0,83 0,88 0,4 0,2 0 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, activité physique, antécédent ORL, séances de kiné resp., comorbidités

Use of antibiotics (IVAS) 1,8 Tout médecin Médecin traitant 1,6 1,4 1,2 1,15 1,2 1 OR* (IC 95%) 0,8 0,6 0,4 1 0,44 1 0,54 0,2 0 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, activité physique, antécédent ORL, séances de kiné resp., comorbidités

Use of antipyretics (IVAS) 1,8 Tout médecin Médecin traitant 1,6 1,4 OR* (IC 95%) 1,2 1 0,8 0,6 1,13 1 0,53 1,17 1 0,4 0,42 0,2 0 *Sur cette figure, l odd ratio associé à la pratique(allopathique prise comme référence) est représenté grâce à des diagrammes boursiers en ordonné(l intervalle de confiance associé est également représenté), les modèles sont ajustés sur âge, sexe, niveau d éducation, nombre de visites, hospitalisations, activité physique, antécédent ORL, séances de kiné resp., comorbidités

Scientific publications from EPI3 Study Manuscript Journal Calendrier Impact of physician preferences for homeopathic or conventional medicine on patients with musculoskeletal disorders : results from the EPI3-MSD cohort Pharmacoepi Drug Saf 2012 Cct;21(10):1093-101 Management of upper respiratory tract infections by different medical practices, including homeopathy, and consumption of antibiotics in primary care: the EPI3 cohort study in France 2007-2008 PloS One 2013: In Press Homeopathic medical practice for anxiety and depression in primary care: the EPI3 cohort study. 33 Eur J Gen Pract 2013: Under review

Benchmarking the burden of one hundred diseases: results of a nationwide representative survey within general practices. BMJ Open 2011 Nov14;1(2):1(2):e000215 Characteristics of patients consulting their regular primary care physician according to their prescribing preferences for homeopathy and complementary medicine. Homeopathy 2013 e-pub ahead of print Benchmarking clinical management of spinal and nonspinal disorders using quality of life: results from the EPI3-LASER survey in primary care. Eur. Spine Journal 2011 Dec;20(12):2210-6 Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3- LASER survey in France. BMC MSD 2011, Jan 19;12:21 Who seeks primary care for sleep, anxiety and depressive disorders from physicians prescribing homeopathic and other complementary medicine? Results from the Epi3 population survey BMJ Open 2012 Nov22;2(6)