REPORT OF RESULTS · CREC presentation June 13 September 13 AACC presentation June 13 September 13 Preparation of electronic Clinical Report Form (CRF) September 13 October 13

Participant institutions and entities

REPORT OF R E S U LT S

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General information

Protocol code and version:CGC-ADH-2013-01 (17th September 2013, version 14).

Study name:Evaluation of the pharmaceutical services programme for elderly, chronic, polymedicated and non-adherent patients (ADHIÉRETE Programme).

Promoted by:General Pharmaceutical Council of Spain

Sponsored by:Laboratorios Esteve, S. A.

Reference CREC:Clinical Research Ethics Committee of the Basque Country

REPORT OF R E S U LT S

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ADHIERETE

Table of contents

1. Abbreviations .................................................................................... 3

2. Background ...................................................................................... 3

3. Objectives of the study ................................................................... 4 3.1. Main objective ............................................................................. 4 3.2. Secondary objectives ................................................................... 4

4. Design of the study ......................................................................... 4 4.1. Sample size and analysis sample .................................................. 4 4.2. Inclusion criteria .......................................................................... 5 4.3. Exclusion criteria .......................................................................... 5 4.4. Analysis sample .......................................................................... 5

5. Study schedule ................................................................................. 6

6. Description of statistical analysis .................................................... 6 6.1. Presentation/format of the results ................................................ 6

7. Hypotheses and statistical methods ............................................... 6 7.1. Descriptive analysis ...................................................................... 6 7.2. Bivariate analysis ......................................................................... 7 7.3. Calculation of derived variables ................................................... 7 7.4. Analysis of the main objective .................................................... 8 7.5. Analysis of the secondary objectives ............................................ 8 7.6. Significance level, multiple comparisons and multiplicity ....................... 9 7.7. Dropouts and missing data .......................................................... 9

8. Principal investigators and co-investigators ................................ 10

9. Sample ............................................................................................ 12

10. Diseases .......................................................................................... 13

11. Medicines ....................................................................................... 14

12. Adherence ...................................................................................... 15

13. Analysis of DRP/NOM .................................................................... 19

14. Usage problems – Support systems .............................................. 21

15. Quality of life ................................................................................. 22

16. Resources analysis .......................................................................... 22

17. Patient satisfaction ........................................................................ 23

18. Dropout analysis ............................................................................ 23

19. Conclusions .................................................................................... 24

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1 ADHIERETE

AbbreviationsAACC: Autonomous CommunitiesAEMPS: Spanish Medicines and Medical Devices AgencyBV: baseline visitCREC: Clinical Research Ethics CommitteeCRF: Case Report FormDRP: Drug-Related ProblemsEQ-5D: EuroQoL 5D QuestionnaireFV: final visitM-G: Morisky-Green TestMRFU: Medicines Review with Follow-UpNNTT: New Technologies (mobile application)NOM: Negative Outcomes associated with MedicinesPDS: Personalized Dosage SystemsPDS+App: MDS alerting systemPMI: Personalized Medicines InformationV: visitVAS: Visual Analogue Scale

2 ADHIERETE

BackgroundAssociated with the increased life expectancy of recent decades is greater chronicity and greater demands placed on healthcare services and medicines.

Healthcare for chronic patients is a policy priority for the Ministry of Health, Social Services and Equality (Strategy for handling chronicity in the National Health System - June 2012), which recommends a systematic review of medication in an effort to detect problems involving medicines, such as the lack of adherence to treatment.

Although the adherence rate can vary greatly depending on the pathology, it is estimated that 20-50 % of all patients do not take their medication as prescribed.

In contrast, it has been shown that actions aimed at improving adherence lower long-term healthcare spending by reducing expenses associated with hospital stays and treatment complications.

The pharmacist mission is to attend patients’ needs as these pertain to their me-dication. To fulfill this mission, pharmacists must dispense treatments individually to each patient, evaluate their results on the patients’ health and prevent or resolve any unexpected or undesired outcomes.

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Objectives of the study

3.1. Main objectiveTo evaluate adherence to treatment in patients included in the Programme.

3.2. Secondary objective To detect drug related problems (DRP), in particular non-adherence, so as to di-minish negative outcomes (NOM) and achieve the desired therapeutic goal while maximizing the medication’s safety and effectiveness.

To evaluate the impact of the adherence support services offered in the Programme.

To evaluate the change in the quality of life of the patients in the Programme.

To evaluate the Programme’s impact in terms of cost-benefit.

To assess the impact of the electronic prescription on the Programme’s effective-ness and efficacy.

To evaluate the patients’ satisfaction with the Programme.

4 ADHIERETE

Design of the studyThe Programme was evaluated by means of a naturalistic (pre-post), randomized, prospective, multi-center, community pharmacist interventional study with no control group.

The pharmacists who agreed to take part in the Programme signed an Investigator Commitment. Associated with each pharmacy was a principal investigator and as many co-investigators as designated by the former.

It was estimated that six months of field work would be needed to achieve the sta-ted objectives, with a minimum of one monthly visit per patient in the Programme.

Each community pharmacy had to recruit five patients, of whom two would use Personalized Dosage Systems (PDS) to support adherence, two would use a mobile application (NNTT) and one would use PDS along with an alert system associated with the PDS (PDS+App). These patients were assigned to each of the three adhe-rence support systems at random by means of a stratified sample for each commu-nity pharmacy.

4.1. Sample size and analysis sampleThe sample size was calculated based on existing studies and considering those patients who adhered to medication regimens at the end of the study using the Morisky-Green (M-G) Test. This yielded an approximate percentage of patients ad-

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hering to their medication at the end of the study of 70 % ± 6 %, with a two-sided confidence interval of 95 %. These assumptions yielded a required sample size of 225 patients.

Assuming five patients were recruited per community pharmacy, a total of 45 pharmacies would be needed. In anticipation of the loss of community pharmacies from the study, and so as to obtain the total number of patients needed, it was deci-ded to involve 60 community pharmacies from the provinces of Badajoz, Barcelona, Bizkaia and Cáceres.

4.2. Inclusion criteria Patients aged ≥ 60.

Chronic and polymedicated (five or more medicines and treatment duration > 3 months) patients.

Patients in whom the Dispensing Service identified a DRP due to non-adherence and/or a NOM of ineffectiveness due to non-adherence.

Patients not adhering to treatments based on the Morisky-Green Test.

Patients who signed the informed consent form.

Patients with a mobile device (smartphone).

4.3. Exclusion criteria Patients not meeting all of the inclusion criteria.

Patients with a medical or psychological condition that could limit their ability to participate in the study.

Patients not expected to cooperate fully.

4.4. Analysis sample The valid sample was defined as the one that included all the patients who met the inclusion/exclusion criteria defined in the protocol.

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5 ADHIERETE

Study schedule

6 ADHIERETE

Description of statistical analysisThe contents of the database were transferred to SAS® datasets for statistical analy-sis. All of the statistical analyses were carried out using the SAS® Statistics Package, version 9.3.

No changes were made to the analyses anticipated in the protocol.

6.1. Presentation/format of the resultsIn general, the average, median, and standard deviation for the continuous variables are shown with one additional decimal place. The maximum and minimum values are shown with the same level of accuracy as the raw data.

For the categorical values, the percentages are shown to one decimal place.

7 ADHIERETE

Hypotheses and statistical methods

7.1. Descriptive analysisDescriptive analyses were carried out for all of the variables. Depending on the va-riable type, are shown:

Start End

AEMPS presentation May 13 June 13

CREC presentation June 13 September 13

AACC presentation June 13 September 13

Preparation of electronic Clinical Report Form (CRF)

September 13 October 13

Recruitment period November 13 January 14

Field work November 13 June 14

Interim analysis August 14 August 14

Statistical analysis September 14 December 14

Report of final results January 15 April 15

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Frequencies and percentages for the categorical variables.

The continuous variables are summarized using the measures of central tendency and dispersion: mean, average deviation, median, 25 % and 75 % percentiles (Q1 and Q3) and extreme values (minimum and maximum).

All of the cases considered are listed in the open comments/remarks fields when deemed of interest.

7.2. Bivariate analysisWhen deemed of interest to the study’s objectives, the relationship between varia-bles was evaluated:

Contingency tables are provided for two categorical variables with columns for the frequency of each category and percentages. Any potential relationship was analyzed using the Chi Square Test or Fisher Exact Test, with the resulting p-value as shown.

Descriptive statistics by group are given for one numerical and one categorical variable. Potential associations were analyzed using the T-test, ANOVA test or the non-parametric Wilcoxon or Kruskal-Walls tests.

The Pearson or Spearman correlation, as well as its p-value, is given to assess the relationship between two numerical variables.

7.3. Calculation of derived variables Age: (Date of birth - date of baseline visit)/365.25

EQ-5D Questionnaire (Shaw, 2005):

– All patients start out with a value of 1.

– If the answer to any question is not 1, apply: -0.081.

– If the answer to any question is 3, apply: -0.269.

– Based on the answer:

– If the answer to any question is missing, the index cannot be calculated.

Answer

2 3

Question 1 -0.069 -0.314

Question 2 -0.104 -0.214

Question 3 -0.036 -0.094

Question 4 -0.123 -0.386

Question 5 -0.071 -0.236

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Patient Satisfaction Questionnaire:

– Questions 1, 3, 4, 5, 6, 7 and 9 were scored from 3 to 0, question 6 was only valid for patients in the PDS or PDS+App groups, and 7 only for patients in the NNTT group.

– Questions 2, 8 and 10 were scored as a 3 if Yes and 0 if No.

– The overall score was obtained by adding each score to the questions.

7.4. Analysis of the main objective Adherence was evaluated using the Morisky-Green test. The trend in the percentage of patients who adhered to their treatments was evaluated over the course of the different visits.

The evaluation was carried out globally using a mixed-effects model and differences in adherence were analyzed between the different groups.

7.5. Analysis of the secondary objectives To detect DRP so as to diminish NOM and achieve more safety and effec-tive medicines:

A descriptive analysis was conducted of the DRP and NOM at the patient level and for both the DRP and NOM. A descriptive analysis was conducted for each support group.

To evaluate the impact of the adherence support services offered in the Programme:

A descriptive analysis was conducted of the information collected in the CRF sec-tion on assessing adherence. A descriptive analysis was conducted for each su-pport group.

To evaluate the change in the quality of life of the patients included in the Programme:

The quality of life of the patients included in the Programme was evaluated using the EuroQoL 5D-3L Quality of Life Questionnaire.

The progress of the quality of life was evaluated in patients based on the answers to the questionnaires given during the V1 and final visits. This was done by using the T-Test for paired data or, if the required conditions were not satisfied, the non-parametric Wilcoxon Test.

Potential differences in the progression of the quality of life were also evaluated for the different support groups.

To evaluate the Programme’s impact in terms of cost-benefit:

To evaluate the cost-benefit, the data collected in the CRF regarding communi-cation with the doctor, healthcare resources and time devoted to the visit were described. A descriptive analysis was conducted for each group.

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To assess the impact of the electronic prescription on the Programme’s effectiveness and efficacy:

A descriptive analysis was conducted for each type of DRP and NOM depending on whether it was corrected or not.

A mixed-model effect was used to determine if these percentages varied by group.

To evaluate the patients’ satisfaction with the Programme:

The patients’ satisfaction with the Programme was evaluated by using the answers provided on the relevant satisfaction questionnaire.

A global descriptive analysis of the answers in the satisfaction questionnaire was carried out to determine if there were differences in the answers based on the respondent’s group.

7.6. Significance level, multiple comparisons and multiplicity

The significance level adopted for all the tests was two-sided 0.05.

No adjustments or corrections were made for multiple comparisons or for multiplicity.

7.7. Dropouts and missing dataNo kind of data allocation was performed. Only the patients observed were analyzed, with a description provided for the number of data missing from each analysis.

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Report of results

8 ADHIERETE

Principal investigators and co-investigators

BADA

JOZ

BERMEjO GARCíA, MARíA ÁNGElES llORENTE CANCHO, CARMEN

CABAllERO lEDO, AlEjANDRA MARTíNEz DE lA CONCHA, jUANCachola Maldito, Vanda María

FUENTES PAlACIOS, MARíA PASIóN NOA RíOS, jOSé MANUEl

GERVASINI RODRíGUEz, CRISTINA PUlGARíN MORUNO, MANUEl

GRIDIllA SAAVEDRA, jAVIER VERDASCO MUñOz, VERóNICA

BARC

ELO

NA

ANDRéS PERERA, ANNA M.ª IRACHETA TODO, MONTSERRAT

BARAU GERMèS, MERCèTribo Alcobe, Gemma

PARDO REGUANT, CARMESánchez Cepero, Montserrat

BOVET PlA, TURATrabe Sánchez, Marta

PIERA SERRA, GlORIACarrasco López, Sandra

Sajko, Jani

CARBONEll BRUFAU, MERCè RIUS SAlA, MERCè

DAlMASES BAlAñA, jORDI ROIG MARTíNEz, MARTA

FONT OlIVET, ANNA M.ªRius Font, Laura

SURROCA REBéS, AINARamón Muñoz, Antonio

IBÁñEz FERNÁNDEz, jOSéAlgueró Arnal, Inés

VECIANA BORRàS, M.ª CONCEPCIóRabella Foz, Eulalia

Veciana Botet, Marina

BIZK

AIA

AMAYUElAS CElAYA, lOURDESLores Santamaría, Cristina

Martínez Monge, Almudena

GABIlONDO zElAIA, ITXASNEAureguizar Ajuriagogeascoa, Joana

ANDRACA ITURBE, IRUNEAndraca Iturbe, Leire

Gallardo Escudero, AlbaGaztelurrutia Laves, LeireMerino Alonso, OihaneSánchez Carrillo, LorenaSolaun Bilbao, Estíbaliz

GONzÁlEz AlVÁREz, lEONARDOCarpintero Díaz, Sonia

Davalillo Cadabal, ArgiñeGarcía Amann, FátimaGonzález Cavia, MaríaSalazar Lecue, Naiara

ANGOITIA GARCíA, ÁNGElAIrastorza Hierro, MartaOuro García, Raquel

GOYENECHEA UzKANGA, ITzIARLamela Macías, Cristina

ARTECHE ARANzAMENDI, ElENAEgaña Bilbao, Maider

lINAzA PEñA, IñAKIFernández Fernández, Mónica

Galiana Gálvez, RafaelLinaza García, AmayaNieto Hierro, M.ª Jesús

BENITO BUTRON, M.ª PIlARSorrigueta Gredilla, Casilda

lóPEz REGUEIRO, SOFíAFernández Ibáñez, Irati

García Ordoñez, Alberto

CASTIEllA lECUONA, ElENAAburto Goiri, Avelina MaríaRomero Valverde, Edurne

MARTíNEz AzUMENDI, GERMÁNAzpiazu Carmouze, Marta María

Larrinaga Santamaría, Izaskun

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Coordinators from Pharmacy Chambers

BADAJOZ Javier Gridilla

BARCELONAMercè Barau

Mónica Gallach

BIZKAIABlanca Díez

Nerea Seisdedos

CÁCERES Isabel Rodríguez

CGCOF

Carmen Peña

Ana Aliaga

Luis Amaro

Carmen Recio

Laura Martín

Carmen Megía

Raquel Varas

BIZK

AIA

CORTINA MENDIzABAl, VIRGINIAAlcalá Etayo, Arantzazu

Domenech Alfonso, EiderGómez Fernández, Beatriz

MÚGICA VAN HERCKENRODE, ElSAGómez Suárez, Janelis

DíAz RAMóN, RUTH lUCíABengoa Castellanos, Isabel

Capitán Osorio, MaríaDávila Carmona, Vanesa

Pérez Pérez, MikelRamón Ferrer, M.ª Lucía

UNCETA SUÁREz, MANUElRodríguez Ferreras, Adrián

Suárez Lacalle, PaulaZuloaga Pérez, Susana

ERAzO PRESSER, FlAVIA MARINARodrigo Gutiérrez, JonSáenz Álvarez, María

URIARTE GARCíA-BORREGUERO, jUANGallego Castañiza, Francisco Javier

CÁCE

RES

CERRO SIERRA, M.ª ISABEl

HERNÁNDEz RINCóN, jUAN jOSECasero, Ana

Díaz, EsperanzaHernández, Mª Pilar

ClAROS VICARIO, PEDROClaros, SaraCuéllar, Ruth

Martínez-Ancín, Ana M.ªReixa, Mónica

jARAíz ÁRIAS, jUAN FERMIN

FERNÁNDEz lORO, ISABEl-FIDElA jARAIz FERNÁNDEz, FRANCISCO

GARCíA DE CASASOlA GARCíA, jUAN FRANCISCOVICENTE MUñOz, ROSA MARIA

Gómez, MercedesGómez, Miriang

GóMEz VICENTE, jAVIER

Tota

l

51 community pharmacies 116 community pharmacists

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Report of results

9 ADHIERETE

Sample 174 patients recruited.

114 patients suitable for analysis.

60 recruited patients excluded from the analysis for not satisfying a selection criterion or for leaving it blank.

74 patients completed the study.

40 patients completed the study early, with most withdrawing during the third visit. The problem cited most often involved the use of new technologies (22 pa-tients - 59.5 %). The dropouts by group totalled 9 in the PDS group, 27 in NTTT and 4 in PDS+App.

The distribution of valid patients by province was:

– Badajoz: 22 patients (19.3 %)

– Barcelona: 31 patients (27.2 %)

– Bizkaia: 39 patients (34.2 %)

– Cáceres: 22 patients (19.3 %)

The distribution of valid patients based on the level of polymedication was:

– No. of patients taking 5 to 8 medicines: 64 patients (56.1 %)



– No. of patients taking over 17 medicines: 2 patients (1.8 %)

– The average number of medicines per patient was 8.7 (standard deviation of 2.9).

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10 ADHIERETE

DiseasesThe distribution of the most prevalent diseases among the valid patients included in the study was

The remaining diseases were distributed as follows::

1. Hypertension 74.3 %

2. Hypercholesterolemia 55 %

3. Cardiovascular disease 52.3 %

4. Diabetes 30.3 %

5. Pain 27.5 %

6. Depression 18.3 %

7. Anxiety 15.6 %

8. Osteoporosis 14.7 %

9. Arthritis/Arthrosis 11 %

10.Renal impairment 5.5 %

1. Respiratory, thoracic and mediastinal disorders 15,6 %– COPD 6,4 %– Asthma 2,8 %

2. Infections: 13,8 %– Respiratory infections 3,7 %– Nasopharyngitis 2,8 %

3. Gastrointestinal disorders: 11,9 %

– Hyperchlorhydria 5,5 %

– Constipation 1,8 %

4. Nervous system disorders 11 %

– Alzheimer 3,7 %

– Parkinson 2,8 %

5. Breast/reproductive disorders (prostate problems) 10,1 %

6. Metabolism/nutrition disorders 8,3 %

– Hyperuricemia 2,8 %

– Obesity 1,8 %

7. Eye disorders 7,3 %

– Glaucoma 4,6 %

8. Blood and lymphatic system disorders (anaemias) 6,4 %

9. Medical and surgical procedures 5,5 %

10. Traumatic injuries 4,6 %– Sprained ligaments 1,8 %

11. Ear and labyrinth disorders 4,6 %

– Vertigo 3,7 %

12. Endocrine disorders 4,6 %

– Hypothyroidism 3,7 %

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Medicines

ANATOMICAl GROUP No. of meds. Therapeutic subgroup No. of meds.

AALIMENTARY TRACT AND METABOLISM

257 (20.79 %)

A01 STOMATOLOGICAL 22 (1.78 %)

A02MEDICINES FOR ACID RELATED

DISORDERS116 (9.38 %)

A03MEDICINES FOR FUNCTIONAL

GASTROINTESTINAL DISORDERS7 (0.57 %)

A06 MEDICINES FOR CONSTIPATION 7 (0.57 %)

A07ANTIDIARRHEALS, INTESTINAL

ANTIINFLAMMATORY/ANTIINFECTIVE AGENTS

4 (0.32 %)

A10 MEDICINES USED IN DIABETES 75 (6.07 %)

A11 VITAMINS 9 (0.73 %)

A12 MINERAL SUPPLEMENTS 17 (1.37 %)

BBLOOD AND BLOOD FORMING ORGANS

108 (8.74 %)B01 ANTITHROMBOTIC AGENTS 84 (6.79 %)

B03 ANTIANEMIC PREPARATIONS 24 (1.94 %)

C CARDIOVASCULAR SYSTEM 423 (34.22 %)

C01 CARDIAC THERAPY 26 (2.10 %)

C02 ANTIHYPERTENSIVES 17 (1.37 %)

C03 DIURETICS 61 (4.93 %)

C04 PERIPHERAL VASODILATORS 5 (0.40 %)

C05 VASOPROTECTIVES 2 (0.16 %)

C07 BETA BLOCKING AGENTS 54 (4.37 %)

C08 CALCIUM CHANNEL BLOCKERS 39 (3.16 %)

C09AGENTS ACTING ON THE RENIN-

ANGIOTENSIN SYSTEM110 (8.90 %)

C10 LIPID MODIFYING AGENTS 109 (8.82 %)

D DERMATOLOGICALS 4 (0.32 %) D07CORTICOSTEROIDS, DERMATOLOGICAL

PREPARATIONS4 (0.32 %)

GGENITO-URINARY SYSTEM (INCL. SEX HORMONES)

33 (2.67 %)G03

SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM

3 (0.24 %)

G04 UROLOGICALS 30 (2.43 %)

H HORMONE THERAPY 23 (1.86 %)

H01PITUITARY AND HYPOTHALAMIC

HORMONES 1 (0.08 %)

H02 CORTICOSTEROIDS FOR SYSTEMIC USE 5 (0.40 %)

H03 THYROID THERAPY 16 (1.30 %)

H05 CALCIUM HOMEOSTASIS 1 (0.08 %)

JANTIINFECTIVES FOR

SYSTEMIC USE14 (1.13 %) J01 ANTIBACTERIALS FOR SYSTEMIC USE 14 (1.13 %)

LANTINEOPLASTIC AND IMMUNOMODULATING

AGENTS7 (0.57 %)

L01 ANTINEOPLASTIC AGENTS 2 (0.16 %)

L02 ENDOCRINE THERAPY 5 (0.40 %)

MMUSCULO-SKELETAL

SYSTEM46 (3.72 %)

M01ANTIINFLAMMATORY AND

ANTIRHEUMATIC PRODUCTS21 (1.70 %)

M03 MUSCLE RELAXANTS 1 (0.08 %)

M04 ANTIGOUT PREPARATIONS 14 (1.13 %)

M05MEDICINES FOR TREATMENT OF BONE

DISEASES10 (0.81%)

The patients used a total of 1236 medicines during the study. Their distribution, according to the Anatomical Therapeutical Chemical Classification (ATC) System, was as follows:

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12 ADHIERETE

Adherence

General M-G Evolution: from 35 % of adherent patients at the V3 to 75.7 % of adherent patients at the FV. Starting from 0 % of compliant patients at the BV. Yielding a p<0.0001 for both the difference between overall visits and the difference between v3 and the FV.

M-G by group: A mixed-effects regression model was adjusted to evaluate the effects of the visits and the groups in patient adherence as per the M-G Test. No evidence was found of different trends over the course of the visits by group type (p=0.2870), but statistically significant differences were found between visits (p<0.0001) and between groups (p=0.0114). The percentage of adherent patients increased in all three groups with each additional visit, though these percentages were higher in the MDS group, followed closely by the PDS+App group. The NNTT group was significantly lower.

The adherence trend in the PDS group went from 51.1% at V3 to 82.9 % at FV (p=0.0002), from 9.1% at V3 to 57.1 % at FV for the NNTT group (p=0.0034) and from 39.1 % to 73.7 % for the PDS+App group (p=0.0037).

Checks were also carried out to see if there were differences between V3 and FV overall (p<0.001) and separately for each group. Significant differences

ANATOMICAl GROUP No. of meds. Therapeutic subgroup No. of meds.

N NERVOUS SYSTEM 240 (19.42 %)

N01 ANESTHETICS 2 (0.16 %)

N02 ANALGESICS 60 (4.85 %)

N03 ANTIEPILEPTICS 19 (1.54 %)

N04 ANTI-PARKINSON MEDICINES 9 (0.73 %)

N05 PSYCHOLEPTICS 79 (6.39 %)

N06 PSYCHOANALEPTICS 66 (5.33 %)

N07 OTHER NERVOUS SYSTEM MEDICINES 5 (0.40 %)

PANTIPARASITIC PRODUCTS,

INSECTICIDES AND REPELLENTS

1 (0.08 %) P01 ANTIPROTOZOALS 1 (0.08 %)

R RESPIRATORY SYSTEM 52 (4.21 %)

R01 NASAL PREPARATIONS 3 (0.24 %)

R03MEDICINES FOR OBSTRUCTIVE AIRWAYS

DISEASES43 (3.48 %)

R05 COUGH AND COLD PREPARATIONS 5 (0.40 %)

R06 ANTIHISTAMINES FOR SYSTEMIC USE 1 (0.08 %)

S SENSORY ORGANS 25 (2.02 %)S01 OPHTHALMOLOGICALS 24 (1.94 %)

S02 OTOLOGICALS 1 (0.08 %)

V VARIOUS 3 (0.24 %) V03 ALL OTHER THERAPEUTIC PRODUCTS 3 (0.24 %)

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were found in every case, which indicated that the percentage of adherent patients at the end of the study was higher.

Effects of gender, age (60-75; 76-89) and number of medicines (5-8; more than 8) in M-G:

No differences were found in the groups based on gender (p=0.8071) or in the trend over the course of the visits (p=0.5563). The percentage of adherent patients was also unchanged based on gender (p=0.3849). Equivalent results were found in the analysis carried out based on age group (60-75 vs. 76-89, p=0.4176; p=0.5393; p=0.8523).

The number of medicines was also compared. No evidence was found of any differences between the groups based on the number of medicines taken (p=0.5767), though statistically significant differences were found in the interac-tion between visits and the number of medicines, indicating that the trend in the number of adherent patients over the course of the visits changed based on the number of medicines taken. Statistically significant differences existed based on visits for patients on 5-8 medicines (p<0.0001), though no significant differences were found in patients taking more than 8 medicines (p=0.1063). The percentage of patients in each group increased with each visit, though the increase for pa-tients on more than 8 medicines was smaller, making it statistically insignificant.

Relationship between variables associated with compliance (visits, support group and number of medicines taken) in M-G:

No differences were found in the groups based on the number of medicines (p=0.6809) or in the trend over the course of the visits (p=0.1721). Evidence was found, however, of different trends over the course of the visits based on the number of medicines (p=0.0012). Differences were also found based on the group (p=0.0271).

To understand the degree of association between these factors and adherence with the medication regime, the odds ratio (OR) of the different effects were estimated.

Support group:

• The PDS group was 3.87 times more associated with compliant patients than the NNTT group (CI 95 % = 1.53- 9.76 times more associated - significant).

• The PDS+App group was 2.79 times more associated with adherent patients than the NNTT group (CI 95 % = 0.97- 8.03 times more associated - not signi-ficant).

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Visits:

• Patients on 5-8 medicines:

– The adherent patients were 3.71 times more associated with V4 than with V3 (CI 95 % = 2.03- 6.80 times more associated - significant).



– The adherent patients were 20.57 times more associated with FV than with V3 (CI 95 % = 7.68- 55.07 times more associated - significant).

• Patients on more than 8 medicines:

– The adherent patients were 1.36 times more associated with V4 than with V3 (CI 95 % = 0.79- 2.33 times more associated - not significant).



– The adherent patients were 1.83 times more associated with FV than with V3 (CI 95 % = 0.96- 3.51 times more associated - not significant).

These results show that the relationship between visits varied based on the num-ber of medicines taken. In the patient group with 5-8 medicines, the higher num-ber of visits was associated with more adherent patients. In contrast, in the patient group with more than 8 medicines, the majority of the visits were approximately two times more associated with adherent patients than V3, but this association did not increase with a higher number of visits.

M-G by province:

The trend in the M-G Test between V3 and FV by province was:

– Badajoz: from 15.8 % to 71.4 % p=0.0012;

– Barcelona: from 13.3 % to 59. 1% p=0.0005;

– Bizkaia: 61.8 %-80.8 % p=0.1114;

– Cáceres: 40.0 %-100.0 % p=0.1114

Reasons for non-adherence: in the BV, the reasons for non-adherence given by patients were as follows, from highest to lowest: “forgetting to take the medi-cation”, “thinking it was unimportant to take the medication every day”, “other reasons”, “the medication makes the patient feel discomfort”, “not picking up the medication on time”, “using a dosage higher or lower than prescribed”, “di-fficulties using the medication”. It is worth noting that no patient in the study

18

Report of results

mentioned “not being able to afford the medication” as a reason for non-adhe-rence. In the FV, the reasons for non-adherence by non-adherent patients were as follows, from highest to lowest: “forgetting to take the medication”, “thinking it unimportant to take the medication every day”, “other reasons”, “not picking up the medication on time” and “difficulties using the medication”. The “using a dosage higher or lower than prescribed” and “the medication makes the patient feel discomfort” reasons for non-compliance disappear from the baseline to the final visit.

Evolution in medication intake: refers to a medication returned by the patient in a PDS or intakes not confirmed in the NNTT application. An improvement was noticed over the study, with values going from 62.1 % in V3 to 89.2 % in VF (p<0.0001).

Although the effect of increasing adherence results from using both estimating strategies (M-G and medication intake), the specific data do not match. Additio-nal studies would be required to evaluate this effect.

Evolution in medication intake by groups: the percentage of patients who took all the medication increased with the number of visits. No evidence was found of a different trend based on the group (p=0.0678). As for the effect of the visits and the group on the percentage of patients who took all their medication, both were sta-tistically significant (visits p=0.0003, group p=0.0029). The percentage of patients who took their medication increased overall with the number of visits, with the PDS and PDS+App groups exhibiting higher percentages than the NNTT group.

Considering separately the visit effect on each group, the NNTT and PDS+App groups did not exhibit a statistically significant visit effect (p=0.4456, p=0.1291). This agrees with the previous observation that the overall visit effect was the same for all three groups and that any differences were insignificant. This is perhaps due to the presence of a significant interaction between the number of visits and the group, but it was unable to detect it.

When analysing the evolution in the intake of medication by groups between V3 and FV, we see that there was an improvement in the PDS group in the percentage of patients taking their medicines, which went from 72.3 % in V3 to 95.1 % in FV (p=0.0028). A positive trend was also noted in the NNTT group, which went from 36.4 % in V3 to 64.3 % in FV, though the values between the visits were variable and the difference was not significant (p=0.0620). The PDS+App group also saw an improvement, going from 78.3 % in V3 to 94.7 % in FV, though it too was not significant, with variable figures between visits (p=0.0821). Both the initial (V3) and final (FV) percentages were higher from the start for the PDS and PDS+App groups. Their percentages were also very similar, meaning these groups exhibited an advantage over the NNT group in terms of medication intake.

19

ADHIERETE

Medication intake by provinces

The evolution in the medication taken between V3 and FV by province was:

– Badajoz: from 47.4 % to 71.4 % p=0.1669;

– Barcelona: from 66.7 % to 81.8 % p=0.2236;

– Bizkaia: 70.6 %-100 % p=0.0032;

– Cáceres: 55.0 %-100 % p=0.0117.

13 ADHIERETE

Analysis of DRP/NOM Incidences: of the 257 DRP detected, 230 (89.5 %) involved the medication and 27 (10.5 %) involved the association between medicines/health problems. The most frequent incidences involving medicines were associated with proton pump inhibitors (8.7 % of all medication-related reasons), followed by angiotensin converting enzyme inhibitors (6.52 %) and HMG-CoA reductase inhibitors (6.52 %), and the most frequent involving health problems were hypertension (18.52 %), followed by pain (11.11 %), undefined disorder (11.11 %) and hypercholesterolemia (11.11 %).

General DRP detected: 257 problems related to the use of medicines were detec-ted in 114 patients. 139 (54.1 %) of the DRP involved non-adherence, 29 (11.3 %) interactions, 26 (10.1 %) inappropriate dosage, treatment and/or duration, 21 (8.2 %) incorrect administration of the medicine, 11 (4.3 %) probability of adverse effects, and 10 (3.9 %) personal characteristics, among others. From the standpoint of the patients, a DRP involving non-adherence was detected in 63.2 %, inappropriate dosage, treatment and/or duration in 14 %, incorrect administration in 12.3 %, interactions in 8.8 % and probability of adverse effects in 7.9 %, among others.

DRP detected by group: the analysis by group reveals that the number of DRP detected was 116 for the PDS group, 81 for the NNTT group and 60 for the PDS+App group. In all of them, the most common DRP was non-adherence (53.4 %, 59.3 % and 48.3 % respectively), followed by interactions, incorrect administration of the medicine, and inappropriate dosage, treatment and/or duration in the PDS group (12.1 %, 6.9 % and 6.9 % respectively), inte-ractions, inappropriate dosage, treatment and/or duration and incorrect administration of the medicine in the NNTT group (9.9 %, 9.9 % and 7.4 % respectively), and inappropriate dosage, treatment and/or duration, inte-ractions and incorrect administration of the medicine (16.7 %, 11.7 % and 11.5 % respectively) in the PDS+App group.

20

Report of results

NOM detected: 257 health problems not controlled detected in 114 patients. 131 involving ineffectiveness (50.9 % - 27.2 % quantitative and 23.7 % non-quantitative), 69 (26.8 %) need for medicine, 46 safety risk (17.9 % - 9.3 % quantitative and 8.6 % non-quantitative), and 11 (4.6 %) unneces-sary medicines. From the standpoint of the patients, 65.8 % were affected by ineffectiveness, 35.1 % by the need for the medication due to an untreated health problem, and 26.3 % by safety risks.

NOM detected by group: the analysis by group reveals that the number of NOM detected was 116 for the PDS group, 81 for the NNTT group and 60 for the PDS+App group. Among the NOM identified, ineffectiveness was the most reported by all the groups (51.7 % PDS, 53.1 % NNTT and 46.7 % PDS+App). This was followed by need for medicine, the next most reported NOM (29.3 % PDS, 23.5 % NNTT and 26.7 % PDS+App), and then, in all three groups, by safety risks (13.8 % PDS, 18.5 % NNTT and 25 % PDS+App).

Interventions: 257 interventions were proposed. 154 (59.9 %) involving provi-ding information, healthcare education (30.7 %) and personalized medi-cine information (PMI) (29.2 %). 13.6 % of the cases were referred to the Medicines Review with Follow-Up Service (MRFU), 8.2 % were referred to the doctor, informing of the DRP/NOM, 5.4 % were referred to the doctor, proposing a change in the treatment, in 8.2 % of the cases another type of intervention was proposed and in 4.7 % of the cases no action was taken. From the standpoint of the patients, 71.1 % received information (by way of healthcare education or PMI), 15.8 % were referred to MRFU, 13.2 % were re-ferred to the doctor, informing of the DRP/NOM, and 11.4 % were referred to the doctor, proposing changes in the treatment.

Interventions by group: in the analysis by group, the main intervention propo-sed (60.3 % in PDS, 69.1 % in NNTT and 52.1 % in PDS+App) continued to be that of providing information (PMI and healthcare education).

Results of the interventions: in general, the pharmacist’s intervention resulted in an increased percentage of patients in the improved + improved and resol-ved categories, with values going from 59 % in V3 to 78.5 % in FV (p<0.0001). In terms of problems resolved, the percentage of problems detected over the course of the visits not only diminished, but those reported were resolved, going from 27.7 % in V3 to 61.1 % in FV.

Results of interventions by groups: no evidence was found indicating different results from the interventions by group (p=0.0855). The effect of both the visits

21

ADHIERETE

on the one hand and of the support group on the other on the result of the interventions was statistically significant (visit p<0.0001, group p=0.0093). The percentage of “no change” and “improvement” results decreased in every group, while the percentage of “improved and resolved” increased, with the PDS and PDS+App groups having a higher percentage of positive results than the NNTT group.

In the PDS group, the interventions with improvement and resolved increased with the number of visits, going from 30.7 % in V3 to 64.4 % in FV (p<0.001). In the NNTT group, the percentage of patients with improvements and problems re-solved went from 12.3 % in V3 to 42.9 % in FV (p=0.004), and in the PDS+App group from 40.0 % to 63.4 % (p=0.0146). The association between the groups and the top categories of the result of the intervention (improved and improved and resolved) was strongest in the PDS group than in the PDS+App and NNTT groups. The association in the PDS group also increased with the number of visits, which did not happen in the other groups.

Analysis of the relationship between the electronic prescription and the result of the intervention: Due to insufficient statistical power, this analysis was unable to be carried out.

14 ADHIERETE

Usage problems – Support systems Overall, the PDS and PDS+App groups had few problems using the adherence support systems, with values of approximately 8.1 % to 15.2 %, though this difference was not significant (p=0.4556). For the NNTT group, however, the percentage experiencing problems was considerable, ranging from 71. 4% to 84. 9%, though again the difference was not significant (p=0.3316). It could be said that in general, the use of the PDS was simpler for patients than the use of the NNTT proposed.

Usage problems by province:

– Badajoz: in this case the patients using the PDS did not report any problems. Some problems were detected in the NNTT group, ranging from 28.6 % to 60 %, depending on the visit.

– Barcelona: very few problems with patients using PDS and very high figures for the NNTT (66.7 % to 100 %).

– Bizkaia: likewise, very few problems in the PDS group and high figures for the NNTT group (50 % to 85.7 %).

– Cáceres: the situation was similar in Cáceres, with 100 % of the NNTT group reporting problems in every visit during the study.

22

Report of results

15 ADHIERETE

Quality of live EuroQol -5D Questionnaire: the average difference between FV and V1 for each patient was 0.078 points (0.651 in V1 and 0.721 in FV). This observed di-fference is significant (p=0.002). The patients, therefore, exhibited a moderately good quality of life, which was improved through the support systems.

VAS score: the average difference between FV and V1 for each patient was 5.5 points (60.8 in V1 and 66.4 in FV). This observed difference is significant (p=0.0029). These values indicate that there were patients with an average or moderately good quality of life that was significantly improved by the support systems.

VAS score by group: the group analysis of the visual analogue scale did not reveal any significant differences between groups (p=0.9134). The quality of life was improved in every group. In absolute terms, the difference was highest in the NNTT group, with a 7.2 point difference between V1 and FV, though this differ-ence is not statistically significant.

16 ADHIERETE

Resources analysis Time devoted to each visit: the average time devoted to a visit was 36.32 minutes. The longest visits were V5, V6 and FV, averaging 40 minutes. These were followed by V4, averaging 38 minutes, V2 and V3, averaging 37 minutes, V1, averaging 34, and finally the BV, averaging 27 minutes.

Significant differences (p=0.0008) were recorded to the time per visit over the course of the study. The later in the study, the more time the pharmacist devo-ted to the visit.

Communications with doctors or other healthcare professionals: the num-ber of communications between the pharmacist and doctor or other healthcare professional over the course of the study was 65. The visit resulting in the most communications was V1. The main channel of communication was the te-lephone, followed by letters and e-mail.

In response to these, 36 communications were sent by the doctor to the phar-macist, but not every communication issued received a response.

Healthcare resources used:

Due to insufficient statistical power, this analysis could not be performed.

23

ADHIERETE

17 ADHIERETE

Patient satisfaction The average overall score on the satisfaction survey used in the study was 81.28/100. In the analysis by group, the score obtained by the PDS group was 83.98, 72.22 by the NNTT group and 82.30 by the PDS+App group. The scores for the two groups that used PDS were very similar. This difference was significant in comparison to the level of satisfaction reported by the patients in the NNTT group (p=0.0067).

18 ADHIERETE

Dropout analysis The number of dropouts varied by group, with the highest percentage of drop-outs in the NNTT group. In order to evaluate the relationship between adherence and the dropout rate, a comparison was done from visits 3 to 6 between those patients completing the study and those that did not. No significant differences were found in any of the three groups when comparing adherence against com-pletion of the study (PDS: p=0.0754, NNTT: p=0.8982, PDS+ App.: 0.3474).

24

Report of results

19 ADHIERETE

Conclusions Once concluded, the analysis of the data from the ADHIéRETE Programme showed that the different support groups were effective, since the percentage of adherent patients based on the Morisky-Green Test, increased signifi-cantly with the number of visits (p<0.0001), the same as the percentage of pa-tients who took all their medicines (p<0.0001). The percentage of DRP/NOM resolved through the pharmacist intervention also increased significantly with the number of visits (p=0.0093). Also worth noting is the patients’ satisfac-tion with the study, with an average score of 81.3/100, as well as the signifi-cant increase in the patients’ quality of life between visit 1 and the final visit (EQ-5D: p=0.0020; VAS: p=0.0029).

The main objective of our study was to evaluate how well patients adhered to medication regimes. The adherence evolution in the PDS group went from 51.1 % at V3 to 82.9 % at FV (p=0.0002), from 9.1 % at V3 to 57.1 % at FV for the NNTT group (p=0.0034) and from 39.1 % to 73.7 % for the PDS+App group (p=0.0037). The percentages were highest in the PDS group, followed closely by the PDS+App group, with the NNTT group being significantly lower. Significant differences were found in every case, however, which indicates that the percenta-ge of adherent patients at the end of the study was higher.

After adjusting a mixed-effect regression model, the results do not reveal any differences between the groups in terms of the improvement in adherence de-pending on the number of medicines being taken by the patient. The main di-fference between groups was between the PDS and NNTT groups, with the PDS group being 3.87 (1.53, 9.76) times more associated with adherent patients than the NNTT group. As concerns the number of medicines, the percentage of compliant patients rose with the number of visits in all three groups when the patients took between 5 and 8 medicines: PDS (Visit3: 40.9 % - Final Vi-sit: 94.4 %), NNTT (Visit3: 0 % - Final Visit: 70 %) and PDS+App. (Visit3: 45.5 % - Final Visit: 90 %). In contrast, the patients taking more than 8 medicines also showed an improvement in adherence, but said improvement did not increase with the number of visits: PDS (around 65 %), NT (around 30 %) and PDS+App (around 50 %).

As for medicines intake, the percentage of patients in all three groups taking all their medication went up (empty blisters in the PDS or the patient in-dicating having taking them in the app) with the number of visits (p=0.0003): PDS (Visit3: 72.3% - Final Visit: 95.1 %), NNTT (Visit3: 36.4 % - Final Visit: 64.3 %) and PDS+App. (Visit3: 78.3 % - Final Visit: 94.5 %). If we compare the groups to one another, we see statistically significant differences between them (0.0067),

25

ADHIERETE

with the PDS and PDS+App groups being 3.89 and 6.95 times more associated, respectively, to taking all their medicines than the NNTT group.

The result of the intervention proposed to solve the DRP/NOM differed with the number of visits (p<0.0001), with the “no change” and “improved” percentages decreasing and the “improved and resolved” percentage increasing. There were statistically significant differences between groups (p=0.0093), with the PDS and PDS+App groups being more associated with positive effects of the interven-tion than the NNTT group.

One important observation to make regarding the study is the dropout rate, with only 65% of all valid patients completing the study. The dropout rate was proportionately higher in the NNTT group, since 27 of the 40 patients who did not complete the study were in this group (67.5 %).

In summary, the adherence support systems significantly improved adhe-rence by non-adherent patients, though to a greater extent in patients with fewer medicines (between 5 and 8), and improved the quality of life of these patients, though these improvements were lower in those patients in the NNTT group.

The failure to adhere to treatments, particularly by chronic and polymedicated patients, has signifi cant medical, fi nancial and social repercussions.

It is estimated to cause 200,000 premature deaths every year in Europe at a cost to healthcare systems of 125 billion euros.

ADHIÉRETE is a research programme developed by the General Pharmaceutical Council of Spain (GPhCS) and the Pharmacy Chambers of Badajoz, Barcelona, Bizkaia and Cáceres to evaluate the pharmacist’s intervention in improving adherence to treatments.

The WHO estimates that 50% of chronically ill patients do not properly adhere to their prescribed treatments2.

Non-adherence costs about 11.25 billion and causes 18,400

deaths a year1.

1.Antares Biofarma Flash Track, 5 February 2013. Financial impact of non-adherence on pharmaceutical costs.

2. WHO, 2003 - Adherence to Long-Term Therapies. Evidence for action.

The pharmacist’s intervention in providing Professional Pharmaceutical Services signifi cantly improves adherence to medicines in elderly, chronic, polymedicated and non-compliant patients.

Patient satisfaction with the Professional Pharmaceutical Service:

8 out of 10

DATA OF THE ADHIÉRETE STUDY

Adherence to treatments improved from 35% to 75.7 %.

8

10

Improved adherence:82.9% for patients in the PDS group after the fi nal visit, versus 57.1% in the mobile app group.

The pharmacist’s intervention was

enhanced through the use of PDS and/or

mobile applications.

57.1 %

Mobile apps

Frequent reasons for non-adherence: forgetting to take the medication, thinking it was unimportant to take the medication daily, discomfort, not picking up the medication on time, dosage not as prescribed and problems using the medication.

Problems and negative results associated with medication were reduced by 33.4 %.

Quality of life increased by 5.5 points on average.

82.9 %

PDS group

The study involved 51 community pharmacies and 114 patients in Badajoz, Barcelona, Cáceres and Bizkaia.

The pharmacist’s intervention reduced DRP/NOM by 33.4% 33 %

257 drug-related

problems (DRP) were detected

10 % inappropriater dosage, treatment and/or duration

8% incorrect administration of the medicine

4.3 % probability of adverse effects

01020304

11.3% interactions

The most frequent DRPs, in addition to non-adherence, were:

257 negative outcomes associated to medicines (NOM) were also detected:51 % ineffectiveness27 % need for the medicine18 % safety risks4 % unnecessary medication

51%

27%

18%

4%

100%

This Programme is part of the European Innovation Partnership for Active and Healthy Aging of the European Commission.

Participant institutions and entities

With the collaboration Supported partners

Documents

REPORT OF RESULTS · CREC presentation June 13 September 13 AACC presentation June 13 September 13 Preparation of electronic Clinical Report Form (CRF) September 13 October 13