THE DIMATCH-HTA STUDY

DETERMINANTS AND IMPACT OF MEDICATION ADHERENCE AND THERAPEUTIC CHANGE IN THE

CONTROL OF ARTERIAL HYPERTENSION

AMONG COHORTS OF IMMIGRANTS AND NON-IMMIGRANTS AT THE PRIMARY CARE LEVEL

Principal Investigator: Evangelista Casimiro Rocha Research team: Paulo Nicola, Mário Carreira, Violeta Alarcão, Paulo Nogueira,

Milene Fernandes, Maria Alves Cortes, Marta Godinho

Scientific consultants: Charles Agyemang, José Pereira Miguel

Unidade de Epidemiologia

Instituto de Medicina Preventiva Faculdade de Medicina de Lisboa

June 2008

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INDEX

SUMMARY …………………………………………………………………….. 3

RESUMO ………………………………………………………………………. 4

BACKGROUND ……………………............................................................. 5

SPECIFIC AIMS ……….............................................................................. 9

METHODS ……………............................................................................. 9

Study Design ……………………………………………………………………... 9

Study Population and Eligibility Criteria ……………………………………. 10

Sampling Process ……………………………………………………………….. 10

Data Collection Process ………………………………………………………... 11

Variables Definition ……………………………………………………………... 12

Measurements and Data Sources …………………………………………….. 15

Sample Size ………………………………………………………………………. 15

Statistical Methods ……………………………………………………………… 16

PRELIMINARY DATA ………………………………………………………….. 17

EXPECTED RESULTS ................................................................................ 20

STUDY TIMELINE AND HUMAN RESOURCES ................................................ 19

ETHICAL ISSUES ....................................................................................... 19

BUDGET AND MATERIAL RESOURCES ……………………………………….. 20

EXPECTED PUBLICATION AND PRESENTATIONS …………………………….. 21

BIBLIOGRAPHIC REFERENCES ……………………………………………….. 22

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SUMMARY

INTRODUCTION: Hypertension is a serious problem of public health since it affects more then 50% of the

Portuguese population above 45 years. Lack of hypertension control is strongly associated with stroke

mortality and acute myocardial infarction, two leading causes of death and morbidity in Portugal. Among

the determinants of failure to control blood pressure, non-adherence and clinical inertia assume major

relevance. Cultural and socio-economic factors and health services access and utilization are critical

aspects underlying non-adherence and clinical inertia. These issues become even more complex when it

comes to hypertensive immigrants, due to the specifics involved in social integration, the migration

phenomenon and the own ethnicity. Both migrant and non-migrant populations are followed at primary

care level, where a strong patient-physician relationship and an integrated management of multiple

chronic diseases are a challenge to physicians. Longitudinal studies are the best approach to evaluate

medication adherence and therapeutic inertia dynamics, providing a better understanding on determinants

able to be intervened.

SPECIFIC AIMS: a) examine potential determinants of medication adherence and therapeutic adjustment;

b) identify multidirectional relations between adherence, inertia and the blood pressure control; c) identify

sub-groups, in each cohort, with high risk of uncontrolled hypertension related to poor adherence and/or

clinical inertia.

STUDY DESIGN: Observational, population-based prospective cohort study of medicated hypertensive

patients, followed at Primary Care Health Centres (PHCC) of the Lisbon Health Region, will be stratified to

two different cohorts, according to their status as immigrants or native.

METHODS: The sampling process will follow a multistage approach, by clusters, aiming to draw a

representative sample from the native and immigrant population who accesses primary care centres in

Lisbon, and their physicians. The final sample will be constituted by 1090 immigrants’ patients from African

Portuguese Speaking Countries and 1090 native medicated hypertensive patients. The inclusion criteria

will be verified through SINUS information system, by asking their physicians and during a phone interview

with the patient. The follow-up period will last for 18 months, and data collection will be performed by face-

to-face and phone interviews. The enrolled participants’ physicians will be asked to fulfil a questionnaire

after each medical appointment. Data collected will allow a longitudinal analysis by using the software

SPSS and R.

EXPECTED CONTRIBUTIONS: With a prospective evaluation of medication adherence and clinical

inertia, it will be identified the impact of key factors such as access and continuity of health care, the

patient beliefs regarding hypertension and antihypertensive medication and the patient-physician

relationship, and of key moments, such as a new medical appointment and time between appointments.

All these results will provide evidence for interventions and recommendations on hypertension

management. Also, by assessing both patients and physicians and their relationships, this study will be

able to examine the value of continuity and personalized care, which are specific values of Primary Health

Care. As we have preliminary results, we will be particularly interested in proposing and testing

interventions aiming to improve high blood pressure control and anti-hypertensive adherence.

KEYWORDS: Hypertension, Medication adherence, Clinical inertia, Migration

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RESUMO INTRODUÇÃO: A hipertensão arterial (HTA) é uma doença crónica que atinge mais de 50% da população portuguesa acima dos 45 anos. O não controlo da HTA está fortemente associado ao acidente vascular cerebral e ao enfarte agudo do miocárdio, identificados como as principais causas de morte e morbilidade no nosso país. A não adesão e a inércia terapêutica têm sido apontadas como dois determinantes major do não controlo da HTA. Sendo multi-dimensionais, ambas estão relacionadas com factores culturais e sócio-económicos e com o acesso e utilização dos serviços de saúde, entre outros determinantes. Estes factores tornam-se ainda mais complexos nos imigrantes hipertensos, devido às características próprias da integração social, do fenómeno migratório e da própria etnia. Os cuidados de saúde primários acompanham ambas as populações, imigrante e não-imigrante, colocando exigências ao nível da relação médico-doente e continuidade de cuidados, bem como na adequação dos cuidados de saúde para as várias doenças crónicas que o doente apresenta. Para compreender o impacto destes factores no controlo da HTA são recomendados estudos longitudinais sobre a dinâmica da adesão e a inércia terapêutica. Da identificação destes factores poderão surgir estratégias de intervenção para melhoria do controlo da HTA.

OBJECTIVOS: a) descrever os determinantes da dinâmica da adesão terapêutica e da mudança terapêutica; b) analisar a relação multidireccional entre adesão, inércia terapêutica e controlo da HTA; c) identificar sub-grupos, em cada coorte, com elevado risco de não controlo da HTA relacionado com a não adesão e/ou inércia terapêutica.

DESENHO DE ESTUDO: observacional analítico, prospectivo e de base populacional, de 2 coortes de imigrantes e não imigrantes, com HTA medicada e seguidos nos Cuidados de Saúde Primários da Região de Saúde de Lisboa.

MÉTODO: O processo de amostragem será multi-etápico, por conglomerados, pretendendo-se uma amostra representativa da população imigrante e não imigrante que acede aos cuidados de saúde primários, bem como dos seus médicos de clínica geral e medicina familiar. A amostra final será constituída por 1090 doentes imigrantes oriundos dos Países Africanos de Língua Oficial Portuguesa e por 1090 doentes de naturalidade portuguesa com HTA medicada. Os critérios de inclusão serão verificados através da informação obtida no sistema de informação SINUS, por questionário aplicado aos médicos e durante uma entrevista telefónica com cada potencial participante. Os doentes de ambas as coortes serão seguidos durante 18 meses, com recolha de informação por realização de entrevistas presenciais e telefónicas. Será pedido aos médicos que preencham um formulário depois de cada consulta com um dos doentes participantes no estudo. A análise dos dados recolhidos será feita com recurso a modelos de estatística adequados, utilizando os softwares estatísticos SPSS e R.

CONTRIBUTOS ESPERADOS: A avaliação prospectiva da adesão e inércia terapêutica irá permitir a identificação de factores-chave que possam ser alvo de intervenção, como o acesso e a continuidade de cuidados de saúde, as crenças sobre a HTA e sobre a medicação e a relação médico-doente; e eventos-chave, como uma nova consulta médica e o tempo entre consultas. Os resultados do estudo darão suporte científico para estabelecer recomendações no controlo da HTA. Além disso, na medida em que o estudo recolhe informação do doente, do médico e da relação entre ambos, será possível avaliar o valor de cuidados de saúde continuados e personalizados, como defendido para os Cuidados de Saúde Primários. Na presença de resultados preliminares, é de particular interesse propôr e testar intervenções que melhorem a adesão à terapêutica e controlo da HTA.

PALAVRAS-CHAVE: Hipertensão, Adesão à terapêutica, Inércia terapêutica, Imigração e saúde.

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BACKGROUND

Cardiovascular diseases are the main cause of death in Portugal, with a mortality rate

among the highest in Europe and the World1. Furthermore, ischemic heart diseases and

cerebrovascular are the third and fifth highest causes for potential years of life lost in Portugal.2

Moreover, international studies showed immigrants are more vulnerable to the effects of

hypertension, in particular with higher prevalence, severity and risk of premature hypertension

by ethnic group, which has been reflected in the differences in morbidity and mortality.3, 4

After age, hypertension is the highest attributable risk factor for cardiovascular diseases,

and it presents a very high prevalence in Portugal. In 2003, a national population-based study

detected hypertensive blood pressure levels in 42.1% of the 5023 adults examined.5 It has been

estimated that 40% of acute myocardial infarction or stroke is attributable to hypertension6. Even

mild or borderline hypertension has been showed to increase stroke’s incidence7. In contrast

with age, hypertension is amiable to prevention and control. This fact justifies the emphasis

given by the Portuguese National Health Plan (NHP) for its prevention and control.8

Also, given the high prevalence of hypertension in the Portuguese population, the National

Program for Prevention and Control of Cardiovascular Diseases recognizes that the control of

high blood pressure is a major objective for the improvement of cardiovascular mortality.9 These

objectives should be achieved by improving the “(…) diagnosis, treatment, follow-up of

hypertensive patients, medication adherence, self-care and self-control of hypertension and

associated risk factors”,10 and by recommending that “(…) scientific studies concerning the prevalence, treatment and control of hypertension in Portugal should be developed.”11

Although effective antihypertensive treatments have been developed in the last decades, studies

have showed that 60-80% of medicated hypertensive patients do not achieve normal blood pressure levels.12 A 2003 population-based national study showed that, among the Portuguese

medicated hypertensive patients, only 28.7% had normal blood pressure levels. This value is in

agreement with other international studies and surveys.13

Medication adherence and clinical inertia are key factors for hypertension control

Among the causes of failure to control hypertension, poor adherence and clinical inertia are top high because of their impact and frequency.14 Adherence has been defined as “the extent

to which a person’s behaviour - taking a medication, following a diet (…) corresponds with

agreed recommendations from a health care provider”. Studies on medication-taking behaviour

have identified low adherence as a primary cause of inadequate control of blood pressure

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(BP) and for having a higher risk of developing complications from coronary heart disease.7, 15

The best available estimates are that poor adherence to therapy contributes to lack of good

blood pressure control in more than two-thirds of people living with hypertension.7

Also, "medication adherence is a dynamic parameter that is not stable over time".16 For instance,

patients with variable adherence often improve compliance around the time of a scheduled clinic

visit but declines thereafter.17 Other key events related to adherence dynamic are acceptance,

representing if whether or not the patient ever starts the dosing regimen, and persistence,

defined as the time between the first and the last dose. Non-acceptance is less studied but it is

recognized by clinical experience,15 while studies on short persistence have pointed out that,

within first year prescription, up to half of newly diagnosed patients quit their antihypertensive

medication.16 All these medication taking parameters will be comprehensively examined during

this study. 18

Antihypertensive medication intensity is another main determinant of blood pressure

control.19 An interest finding is that, in chronic diseases, the problem isn't usually prescribing the

wrong drug but “failure to initiate or titrate medications until important evidence-based clinical

goals are reached”.20 This failure may lead to potentially preventable adverse events, disability,

death, and excess medical care costs.21 Regarding high blood pressure control, it is pointed out

the need to (1) recognize lack of control and (2) initiate and/or intensify treatment until

therapeutic goals are reached.22 Also, hypertension management guidelines reinforces that “the

effective and timely titration to BP control requires frequent visits in order to timely modify the

treatment regimen in relation to BP changes”.23 Despite these recommendations, clinical inertia,

defined as “an office visit at which no therapeutic move was made to lower blood pressure of a

patient with uncontrolled hypertension”24 has a major impact on blood pressure control in

hypertensive patients receiving regular care: a recent cohort study concluded that reducing

clinical inertia would allow to control increased blood pressure in additionally 20% of

hypertensive patients.19 To better evaluate clinical inertia, a sufficient time window should be

considered, to encompass several clinical visits. Furthermore, factors related to physician,

patient and the clinical visit should be considered, such as insufficient time with the patient and

lack of physician training and proactive care.25 Our study will include such design and

longitudinal data collection, to be able to examine and interpret these factors.

Migration, cultural and socio-economic characteristics as challenging factors for

hypertension control

Control and adherence to hypertension medication are complex and multidimensional. We

hypothesize that cultural and socio-economical factors, crucial to the understanding of

hypertension and adherence to anti-hypertensive treatment, and well to the two-way interaction

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with health care services, are major determinants for the control of a chronic disease, such as hypertension. Some of the factors associated to the nature and complexity of migration –

such as individual lifestyle and cultural and environmental conditions – may influence the

adherence to medication in immigrants. We aim to understand how these possible differences

affect the adherence to hypertensive medication, blood pressure control and clinical inertia, by

comparing eventual inequalities among immigrants to non-immigrants.26 Nevertheless, little is

known about migration as a health determinant and this topic has been neglected in the

scientific literature. In Portugal, we have found no published studies about adherence and control of hypertension in immigrants.

It has been demonstrated that African Americans were more likely to have inadequate blood

pressure control when compared to whites.27, 28 Moreover, African were more aware of their

hypertension and more likely to be on treatment if aware of their diagnosis but among those

treated for hypertension, they were less likely to have their blood pressure controlled.29 The

reasons given to explain the poorer hypertension control in different races include genetic

factors, lower aggressiveness of treatment, factors related to lifestyle, diet and stress, side

effects acceptance and access and use of health care.29

Regarding medication adherence, African Americans were more likely to be non-adherent, to

perceive hypertension as more serious and to report increased side effects than whites, with

these factors being related to poorer blood pressure control.27 Non-adherence was shown to be

associated with a lack of a primary care physician and having blood pressure checked in an

emergency room.30 Adherence WHO Report states that race is frequently a predictor of

adherence, regardless of whether the members of a particular race are living in their country of

origin or elsewhere as immigrants. Often, cultural beliefs, fear of discrimination or being

distrusted by medical profession are the reason behind these racial differences.7

All these factors challenge hypertension control, health care and clinical practice. By comparing immigrants and non-immigrants with high blood pressure, we will be able to better understand the impact of socio-cultural characteristics, health care utilization and other important factors in blood pressure control and medication adherence.

Our cohort of immigrant will be restricted to Portuguese Speaking African Countries. Regarding the lately national migration statistic (with age information by country of origin),31 only migrants from the Portuguese Speaking African Countries present a considerable number of individuals above 40 years of age (25%). The great majority of migrants from Brazil and Ukraine (two of the ten top origin countries) have less than 40 years of age. In fact, migration flows from these two countries are more recent than from the African Countries.

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Studying only African migrants is a limitation, but we believe that our findings could contribute for relevant insights concerning barriers to blood pressure control in other minority groups and in the general population. As we stated, the prevalence, severity and impact of hypertension are increased in blacks, and therefore studying African migrants will allow us to better understand those elevated risks.

Purpose and advantages of the current study proposal

Hypertension, as a paradigm of a chronic disease with enormous public heath impact, is a

particularly important social, disease and health care model to understand chronic disease control and management. Including disadvantageous populations, such as immigrants, will

emphasize disease care areas that are fundamental to chronic disease control and

management.

This study will closely follow, for 18th months, a cohort of immigrants and non-immigrants,

allowing measuring and characterizing complex and dynamic phenomena which are major determinants of blood pressure control, such as patient adherence to medication,

health care utilization and clinical inertia. Moreover, this study will characterize the care of hypertension at the primary-care level, which will provide fundamentals data and insights

regarding the impact of primary care in the control of chronic diseases, such as hypertension.

Our team encompasses experienced and knowledgeable researchers, which have lead and

participated in community and primary-care based studies on cardiovascular disease,

medication adherence and health of migrants. This study will allow our country to participate in

international forums and networks were research, clinical care and public health policies for

chronic diseases, primary care, public health, health of immigrants and hypertension.

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SPECIFIC AIMS

We will follow two cohorts of medicated hypertensive patients attending primary health care

clinics, one of immigrants and the other of non-immigrants, in order:

1. To compare migrants and non-migrants concerning the prevalence of controlled

hypertension, antihypertensive medication adherence, patterns of health services

utilization and approaches to hypertension control, adjusted for age, comorbidities, socio-

cultural and economical characteristics.

2. To examine potential determinants of medication adherence and therapeutic adjustment.

In particular, these will be related to:

a. Hypertensive disease, including severity and co-morbidities b. Therapy, namely pharmacological and non-pharmacological approaches c. Health Services, including access, patient-physician relationship and health

system utilization d. Socio-economic aspects e. Patient beliefs and attitudes towards hypertension and therapy

3. To identify multidirectional relations between adherence, therapeutic change, and blood

pressure (BP) control. We will identify situations of clinical inertia. We will test the

following hypotheses:

a. Therapeutic change is associated with medication adherence b. Low adherent patients have a higher probability of uncontrolled BP, inducing

cyclic therapeutic change until higher dosages compensate non-adherence c. Therapeutic change is determinant to BP control in high adherent patients, but not

much so in low adherent patients

4. To identify sub-groups in each cohort with high risk of uncontrolled BP related to poor

adherence and/or clinical inertia.

METHODS

STUDY DESIGN This is an observational population-based prospective cohort study. Medicated hypertensive

patients, followed at Primary Care Health Centres of the Lisbon Health Region, will be stratified to

two different cohorts, according to their status as immigrants or native.

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STUDY POPULATION AND ELIGIBILITY CRITERIA Study participants will:

1) have a clinical record at Primary Health Care Centres from the administrative health

region of Lisbon;

2) have a clinical diagnosis of high blood pressure, as stated by the physician, or recorded in

the clinical medical record;

3) currently be taking antihypertensive medication, as indicated in the clinical medical record,

and confirmed during a visit to the participant;

4) have had their last clinical visit at least six months ago;

5) be aged between 40 and 80 years, included;

6) be responsible for taking their medication;

7) be able to be contacted, with an active phone number and address registered in the

primary health care centre information system;

8) be able to and consent in participate on the study.

We will exclude from this study subjects who are:

1) Institutionalized or those who depend on others to take the medication;

2) Patients with cognitive disorders such as dementia and schizophrenia, as indicated in the

clinical record or perceived during the interview.

3) Having plans to move from the Lisbon Health Region for more than consecutive 4

months within a 18th months period.

4) Patients unable to be contacted by telephone, after 10 attempts, in alternate days, at

different periods of the day.

In this study, immigrants are defined as subjects who were born in Portuguese Speaking African

Countries (Angola, Cape Verde, Guinea Bissau, Mozambique or Sao Tome and Prince), and

have arrived to Portugal after 1980. For the non-immigrants’ cohort, patients must have been

born in Portugal.

SAMPLING PROCESS

The sampling process will follow a multistage approach, by clusters, aiming to draw a

representative sample from the native and immigrant population who accesses primary care

centres in Lisbon Health Region.

a. Sampling of Primary Health Care Centres (PHCC)

Ten, out of 45 PHCC from Lisbon’s Health Region will be randomly selected. All selected PHCC’s

directors will be invited to participate, and any eventual refusal will be replaced by a new PHCC

randomly selected by the same process.

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b. Within PHCC sampling of eligible subjects

For each PHCC, a list of all eligible users will be obtained from SINUS information system

managed by The National Health System Central Administration (ACSS). All eligible users will

be stratified in two lists (natives and non-natives) according to the location of birth (Portugal vs.

Portuguese Speaking African Countries).

c. Within PHCC sampling of participating physicians

Individual will be sequentially drawn from both lists. First 5 physicians reaching 75 users in each

of both cohorts will be selected and invited to participate in the study. Any eventual refusal of

participation by the physician will lead to the next physician reaching the same criteria.

d. Identification of medicated hypertensive patients

Potential medicated hypertensive patients will be identified by asking theirs physicians to

indicate those among the selected subjects. We have shown this identification process to be

superior, when comparing to telephone interview or reviewing the medical record32. Further

selection criteria will be assessed by phone interview.

DATA COLLECTION PROCESS

Data will be collected from following sources and times indicated in table 1.

The follow-up period will last for 18 months, during which it is expected to establish a continuous

relationship between the study participants and the research team by:

(1) Face-to-face interviews each 6 month (4 by participant in 1.5 years of follow-up);

(2) Phone interviews at 3, 9 and 15 months (3 by participant in 1.5 years of follow-up).

This frequency is expected to contribute to keep participants committed during the study and to

clarify any question that may arise by the participants.

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TABLE 1. Data collection sources and periods.

FOLLOW-UP DATA COLLECTION INSTRUMENTS AND SOURCES

VERIFICATION OF ELEGIBILITY

AT BASELINE 3M 6M 9M 12M 15M 18M

Patients’ eligibility form (to be fulfilled by the physician) X

Patients’ eligibility questionnaire (to be fulfilled during phone interview) X

Physician’s questionnaire X X X Patients’ baseline questionnaire (face-to-face) X Patients’ baseline questionnaire – immigrant cohort (face-to-face) X

Clinical records’ form X Social Support Questionnaire (SSQ6) X X X Hospital Anxiety and Depression Scale (HAD) – Portuguese version X X X

EUROPEP – Portuguese version X X Beliefs about Medicine Questionnaire – General and Specific (BMQ) – Portuguese version X X

Illness Perception Questionnaire (IPQ) – Portuguese version X X

Patients’ follow-up questionnaire (face-to-face) X X X Patients’ follow-up questionnaire (telephone interview) X X X

Physicians’ follow-up form During each appointment. Patients’ BP self-measurement and medication adherence diary X X X X

Physicians’ participation consists in fulfilling

(1) A formulary per visit of the enrolled patients, with information about BP values and

changes in therapy.

a. The questionnaires will be annexed to clinical processes and collected monthly.

(2) A mid and final questionnaire regarding attendance to training courses and congresses

related to hypertension, as well as knowledge, attitudes and decision making regarding

management and experience with hypertensive patients.

VARIABLES DEFINITION

a. Outcome measures Blood pressure (BP) Blood pressure record will be collected by three sources of information: (1) patients’ clinical

records and (1.a) form filled by its physicians at each visit, (2) ambulatory BP, in a subgroup of

randomly selected patients, and (3) home BP, performed at all the face-to-face interviews

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(baseline and follow-up period). BP will be measured as a continuous variable and its

classification will be according to 2007 ESH-ESC Practice Guidelines for the Management of

Arterial Hypertension.

Adherence to antihypertensive pharmacological therapy

Adherence will be evaluated as a time-changing parameter, which includes (1) acceptance (in

naïve medicated patients), (2) compliance and (3) persistence. A patient will be classified as

adherent if he accepts to take the prescribed medication, maintains the treatment during the

study period and presents compliance level of 80% or higher.

(1) Acceptance is defined has a dichotomous variable, assuming that a naïve medicated patient

accepts medication when it continues taking it for more than one month.

(2) Persistence is also defined as a dichotomous variable, assuming that a patient persists with

its medication when that is taken until the physician suspends it or the end of study period.

(3) A multi-method approach will be taken in order to access compliance, based on pharmacy

record and self-report:

• At the baseline interview, all the non-naïve patients will be submitted to the following

questions33: “People miss taking their medications for many reasons. Do you have

medicines for which you sometimes miss taking a dose? (..) How many doses might you

have missed in the past 10 days?” (Portuguese) “As pessoas podem falhar os seus

medicamentos por muitas razões. Há medicamentos para os quais, por vezes, falte a

toma de um ou mais comprimidos?” (....) “Nos últimos 10 dias, quantas tomas deve ter

faltado?” These questions had a specificity of 69.8% and a sensitivity of 80%, giving an

overall accuracy of 74.5%, when compared to pill count.33

• All participants will be requested to keep their pharmacy receipts for the duration of the

study period (18 months). This is usual practice as they allow taxes return. Compliance

will be defined as Medication Possession Ratio: sum of the days' supply of medication

divided by the number of days between the first fill and the last refill plus the days' supply

of the last refill. The accuracy of this methodological approach will be defined in a

previous validation study, assuming pill-count as the gold-standard.

Clinical inertia

We will use the O’Connor PJ et al. definition of clinical inertia. Newly added antihypertensive

therapy and increase in the dose of current antihypertensive therapy will be considered

therapeutic changes. Target blood pressure is assumed to be <140/90 mmHg (or <130/80 in

diabetic patients), according to 2007 ESH-ESC Practice Guidelines for the Management of

Arterial Hypertension. Therapeutic change is designated as timely when it occurs within 6 month

from the date of a clinical visit.

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b. Predictors variables

The role of several variables – socioeconomic, health system and health care team, high BP,

treatment and patient-related factors – as determinants of adherence dynamic and therapeutic

change will be collected at baseline and throughout the study. This research team is

experienced in collecting such data and applying these questionnaires, as it has been happening

in other studies.

Socioeconomic-related factors Patients’ baseline questionnaire will allow collecting information regarding socio-demographic

characterization (age, sex, ethnicity, Graffar scale), professional status and income, social

support networks (assessed with Social Support Questionnaire SSQ6), marital status,

educational degree (number of school years concluded). For immigrants, the level of

acculturation will be assessed through the Vancouver index.

Hypertension-related factors From the patients’ clinical medical record, data will be collected regarding the time since the

diagnosis of hypertension, its aetiology and grade (according to European Guidelines); co-

morbidities included in Charlson Co-morbidity Index34 and lipid disorders. At the baseline

interview, the Portuguese version of the Hospital Anxiety and Depression Scale (HAD) 35 will be

applied to all patients enrolled in the study. Cardiovascular risk factors will also be identified at

the baseline interview: alcohol consumption, smoking habits and physical activity practice will be

measured according to Portuguese National Health Survey methodology; height and weight will

allow the calculation of the body mass index.

Treatment-related factors Antihypertensive medication will be assessed each medical appointment throughout the study by

means of a simple, one-page form that the physician will fulfil at the end of each appointment.

Data will be also collected / confirmed at each face-to-face or telephone interview. These data

will pertain to prescription details and allow the computation of the medication’s expenditure.

During face-to-face interview, further information will be collected regarding the patient

involvement in decision’s making, perceived self-efficacy and side-effects, use of over-the-

counter medicines and non-pharmacological treatments.

Health system and health care team-related factors During the patients’ baseline interview, the Portuguese version of EUROPEP will be applied to

access the patients’ satisfaction with primary health care system, including the patient-physician

relationship.36

15

A questionnaire applied to the enrolled physicians will collect information concerning training and

practice in hypertension control, such as, years of clinical practice, enrolment in training

programs on hypertension management, the physician criteria for initiating and intensifying anti-

hypertensive medication and the adoption of guidelines. Other information as needs on

information concerning the management of hypertension, and problems faced when prescribing

antihypertensive medication will also be accessed.

Patient-related factors Patients’ knowledge, attitudes, and lay beliefs about hypertension will be obtained during a face-

to-face interview with the application of Beliefs about Medicine Questionnaire – General and

Specific (BMQ)37 – and Illness Perception Questionnaire (IPQ)38.

MEASUREMENT AND DATA SOURCES Instruments will be pretested and interviewers will have specific training to avoid systematic

errors. Test-retest reliability will be performed in a group of randomly selected patients, being

expected an inter-ratter agreement statistic (Kappa) ≥ 0.85. Adjustment and new testing process

will be conducted to those variables/questions in which Kappa < 0.85. A Manual of Procedures

(or Operations Manual), including definitions and quality control procedures, will be developed

and tested during the pilot study.

SAMPLE SIZE Assuming medication adherence as 80% or more of expected drug intake, a difference of ± 5%

may be detected with a sample size of 907 among the two cohorts (total sample size of 1814).

With this sample size, 907 participants per cohort, and given a statistical power of 80%, it will be

possible to detect relative’s risks of 1.18 or more, or 0.85 or less. For this sample size a

difference among two continuous pair of variables will allow a high power to detect differences.

For instance, to detect differences of blood pressure levels among two groups we will be able to

detect 2 mmHg among two groups (assuming a standard deviation of 5mmHg in each group) in

98.9% of the times. Therefore this samples size will allow powerful multivariate models, even

more as repeated measures will be taken.

To account for lost to follow-up during the study, the total calculated sample size will be

increased in 20%. Therefore, the final sample size will be of 2180 subjects, that is, 1090 per

cohort.

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STATISTICAL METHODS Descriptive and inferential statistics will be performed. 95% confidence intervals will be estimated for parameters of interest and a 5% significance level will be adopted for all statistical hypotheses tests. Analysis will be performed using SPSS and R software. A careful data inspection, cleaning and quality assurance phase will precede statistical analysis. Accordingly to the study main objectives: 1) TO COMPARE MIGRANTS AND NON-MIGRANTS CONCERNING THE PREVALENCE OF CONTROLLED

HYPERTENSION, ANTIHYPERTENSIVE MEDICATION ADHERENCE, PATTERNS OF HEALTH SERVICES

UTILIZATION AND APPROACHES TO HYPERTENSION CONTROL, a description of both cohort will be done, using categorical, parametric and non-parametric descriptive statistics, as appropriate. Prevalence of controlled hypertension will be described according to relevant socio-demographic variables (age, sex, education, economic status) for both groups and 95% confidence intervals will be computed according to the F distribution. Relevant socio-demographic and economical aspects, comorbidities scores and other clinical information (for instance, number of years with hypertension), will be compared among migrants and non-migrants, using chi-square tests for categorical variables, student t-test for parametric or Wilcoxon rank sum test for non-parametric continuous variables, as appropriate. Non-migrants and migrants will be compared regarding dichotomous variables, such as frequency of controlled hypertension, percentage of subjects adherent to antihypertensive medication, etc., using logistic regression modelling, adjusted for age, comorbidities, socio-cultural and economical aspects.

2) TO EXAMINE POTENTIAL DETERMINANTS OF MEDICATION ADHERENCE AND THERAPEUTIC

ADJUSTMENT bivariate and multivariate methods will be used. Bivariated association will be tested using chi-square tests, Fisher Exact Test and binary logistic regression. Multivariated binary logistic regression will be performed to check which factors simultaneously relate with outcome variables.

3) TO IDENTIFY MULTIDIRECTIONAL RELATIONS BETWEEN ADHERENCE, THERAPEUTIC CHANGE, AND

BLOOD PRESSURE CONTROL bivariate and multivariated data analysis will be performed. In bivariated analysis, when adherence or therapeutic chance is considered an dependent

variable, the analysis is identical to the recommended above for potential determinants determination. Of particular interest here is the situation when blood pressure is considered as the variable to be explained (as dependent variable): in such case t-tests and ANOVA will be used, as well as their non-parametric equivalent Mann-Whitney and Kruskal-Wallis tests.

Multivariated approaches, aiming at identifying multiple factors and variables simultaneous associated with blood pressure will consist of multifactorial ANOVA (General Linear Models) and Multilevel Models.

In fact, Multilevel Models (also known as hierarchical linear models, generalized linear mixed models, nested models, mixed models, random coefficient, random-effects models, random parameter models, or split-plot designs) are statistical models of parameters that vary at

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more than one level and are known to be a good very general framework to discover how differences between studies in treatment implementations, research methods, subject characteristics, and contexts related to treatment effect estimates within studies39. These models can be seen as generalizations of linear models, although they can also extend non-linear models.

Multilevel models are known to be very flexible but are also known to be sensible to presence of missing data and low number of information waves (number of time points at which time points were collected). In our study a high number of missing values is not expected. If number of records with missing information is small, listwise selection/deletion will be considered; otherwise data imputation or multiple imputation standard techniques will be considered. In this latter case, sensibility analysis will be performed (analysis with and without imputation) and reported.

4) TO IDENTIFY SUB-GROUPS IN EACH COHORT WITH HIGH RISK OF UNCONTROLLED BLOOD PRESSURE

RELATED TO POOR ADHERENCE AND/OR CLINICAL INERTIA profiles will be generated using multivariate exploratory data techniques: Cluster Analysis and Q Factor Analysis will be conducted.

PRELIMINARY DATA Our research team has experience in working with the primary care setting; examining antihypertensive medication adherence; and studying immigrants’ health. In this section we describe preliminary work and results relevant to demonstrate our proficiency and how this study builds on previous studies.

Immigrants access to primary health care40 There is a lack of studies concerning the health, health care access and equity for the immigrant communities'. In 2007, our research team developed a study about the "Evaluation of Health and Health Assessment of African and Brazilian Immigrants in Portugal" with the objectives of characterizing the health, the access to health care and the health determinants of the African and Brazilian communities living in Lisbon and Setubal Districts, and comparing theses data with the data available from the general population with the 4th National Health Survey.

Individuals were selected through a process of random simple cluster geographical sampling with the help of GIS software (ArcGIS 9.1). The data collection was obtained by teams of interviewers, most of them from the communities in study.

A total sample of 4508 individuals was surveyed, aged between 0 and 87 years old, 51% were women. This population used mainly the National Health Service (86%). Within the last three months, 24% have consulted once a doctor, 14% consulted 2-3 times, and 5% consulted more than three times. The last consultation was mainly in the PHCC (61%).

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Hypertension awareness, prevalence, control and treatment in Immigrants* Furthermore, also in 2007, our research team conducted a study intituled: "Comparison Between Self-Referred Hypertension and Blood Pressure Measurement in African Immigrants and Brazilians", based on a sub-sample from the study described above. Blood pressure measurements were obtained by trained observers using a validated OMROM M6C sphygmomanometer. Additional information’s concerning hypertension and its treatment was collected through a specific questionnaire, during an interview with an interviewer from the same community. The final sample was constituted by a total of 317 individuals, aged between 30 and 83 years old, 61% were women. Overall 45.6% had hypertension. Prevalence of hypertension was higher among African (52.7%) than Brazilian (24.3%) (p<0.001). Overall, 42% of hypertensive patients were aware of their diagnosis. Around 47% of those with hypertension were medicated. Mean years of diagnosis is 11±10.8 and of medication, 10±9.6. Only 19% of hypertensive and 59.7% of hypertensive medicated achieved blood pressure control.

Regarding our approach to study adherence the antihypertensive medication in the immigrant’s cohort, these preliminary results show that hypertensive immigrants seem not to have limited access to health care as they have frequent consultations in the PHCC (a great number had consultations in the previously 3 months of the inquiry). This supports that sampling the immigrant participants may be carried out in the same way as that for the non-immigrants.

How to identify medicated hypertensive patients at Primary Care Health Centres?

The answer to this question was possible with a previous study32 of 250 subjects followed at a primary care centre of Lisbon’s Region, with age ≥ 40 years. To compare advantages and losses of information, independent processes were applied: (1) physicians were asked to identify their patients as with/without hypertension under medication, by answering a brief questionnaire, (2) clinical records were consulted and (3) phone interviews were driven. With the study conclusion, 48% (120 patients) have medicated hypertension identified by, at least, one of the above processes. The physician’s questionnaire allowed the identification of a larger number of medicated hypertensive patients (74.2% of all medicated hypertensive patients) with fewer loss of information.

* Unpublished data.

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Study Timeline and Human Resources

ETHICAL ISSUES

We will take in consideration the following ethical issues:

1. Health care data is sensible personal information. We will de-identify data such as name, birthday, address and telephone contact. Patients and health care providers will be coded with a unique non-identifying number. The database will have protected access (restricted access, password-protected), and servers will be protected with state-of-art software firewalls and anti-virus.

2. Written informed consent will be requested to all participants: a copy of the signed informed consent will remain with the participant. The right to leave the study at any time, and to have all data erased, will be recognized. In order to infer external validity from the data analysis, a small set of non-identifying data (e.g., gender, year of birth) will be used to compare consenting and non-consenting subjects.

3. A permission from Protection Data Portuguese Authority (CNPD) will be required to use centralized databases with individual data. This permission is particularly relevant since we will collect sensible personal and clinical data. This research group is experienced in submitting similar requests to CNPD.

A cross-sectional version of this study has already been approved by the Ethical Committee from the Medical School of the University of Lisbon. Currently, it is pending a request for the modifications related to the longitudinal design.

Month Task 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Human Resources

0. Study protocol and choice of measures

Research team

1. Ethical Committee and administrative permissions

Research team

2. Interviewers selection and training

2 Field coordinators

3. Pilot study 4. Database construction 5. Validation of

compliance measure by pharmacy claims

2 Field Coordinators

2 Interviewers 1 Informatic

6. Sampling Process 1 Study Coordinator

7. Recruitment of medicated hypertensive participants

8. Recruitment of primary care physicians

2 Field Coordinators

6 Interviewers

9. Follow-up period (face-to-face interviews or telephone interviews each 3 months)

2 Field Coordinators

4 Interviewers

10. Data analysis Research team 11. Publications and

divulgation of the study results

Research team

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BUDGET AND MATERIAL RESOURCES

For an expected sample size of 2180 subjects (see sample size calculation), we anticipate the

following budget and material resources:

Item Amount

(Eur) Material

Resources Description

Start-up costs

Consultants 2500 Travel expenses Consultant revision (including travel expenses). Includes 2 visits of 3 days.

Ethical Approval 250 Submission to the Ethical Committee and Portuguese Data Protection Authority

Office material

Phone credits Pilot study 1500

Travel expenses

Pilot study for the validation of study methodology, testing of the data collection and of the procedures manual, in 100 participants (50 per cohort), only at baseline and one follow-visit at 3 months.

Database management 800 Server Database construction and testing, storage and protection.

Office material

Travel expenses Implementation at Primary Care Health Centres (PCHC) 500

Phone credits

Contacts with the PCHCs and general physicians: invitation to the PCHC directors; debriefing; invitation to the physicians. Estimation of 4 visits for 2 persons to 14 PCHC at 4.5 Euros per visit.

Participant-related costs

Physicians' contacts 500 Phone credits Telephone contacts with GP's, during all study phases (110 GP's, 3 visits per GP, 3 phone calls per visit, 0,5 Euros per phone call)

Post expenses

Participants' contacts 30000 Phone credits

Appointment of face-to-face interviews + telephone interviews (2180 participants, 4 visits per participant, 3 phone interviews per participant, 3 phone calls per contact, 0.5 Euros per phone call) (2 letters per participant, 0.5 Euros per letter)

Documentation 5500 Office material Paper questionnaires (~2.5 Euro/participant)

Staff and Analysis costs

Traveling expenses 5000 Travel expenses Public transportation cards for 5 interviewers for 25 months, at 40 Euros per month.

Interviewers' part-time stipend 66000 Stipend 5 part-time interviewers, working a mean of 6 hours/day, for 22 months, at 600 Euros per month.

Statistical Analysis & Report 2500 Statistical analysis performed by a team member and revised by an expert in longitudinal data analysis

Study coordinator 15000 30% time of a study coordinator, for 24 months, for a full-time stipend of 2000 Euros/month.

Field coordinator 10000 30% time of a filed coordinator, for 24 months, for a full-time stipend of 1400 Euros/month.

Travel expenses Participation and presentation in national and international meetings; Publications and divulgation of

results 2500 Meeting registration Publications and divulgation of the study results in

international and national peer-review journals.

sub-total 1 142550

Unexpected expenditures (15%) 21382.5

sub-total 2 163932.5

AIDFM (8%) 16000 Institution overheads.

IMP (10%) 18400 Institution overheads.

Total 198333

200 000

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EXPECTED RESULTS, PUBLICATIONS AND PRESENTATIONS

It is expected to communicate the research’s potential contributions through publications in

international and national peer-review journals, and in international and national meetings

related to areas such as Public Health and Epidemiology, Cardiology, and Immigrant’s Health. In

these areas, the research’s foreseen contributions are

1- Clinical, Public Health, Care for Hypertensive patients, Primary-Care: (1) prevalence

of hypertension control, adherence to antihypertensive medication and clinical inertial; (2)

determinants of hypertension control, adherence dynamic and therapeutic change; (3)

implementation and compliance with current guidelines and recommendations; (4) profile

of the hypertensive patients at the primary-care;

We will be able to describe the dynamics of medication adherence according to important key moments and factors concerning a chronic disease with major public health impact. These key moments are, for example, a new appointment, attending the emergency care or an adverse event. We will measure the impact of key factors, such as patient-doctor relationship and continuity of care, time between appointments, and the physicians’ criteria for intensifying therapy. All these results will provide insights to elements which may be intervened, in order to improve the control of high blood pressure. The importance of these results may be extended to other chronic diseases.

This study will be innovative since it will incorporate the information of both patients and physicians. We will be able to understand how these two perspectives integrate each other: for instance, we will be able to examine if a physician who easily intensifies therapy associates with a more adherent patient; if physicians who like to treat hypertensive patients are associated with patients who belief their antihypertensive medication is effective; if physician who evaluate medication adherence and adverse effects are more likely to have adherent patients. Moreover, this insight is of more value as we will be including primary-care physicians, who are more likely to have long-term relations with their patients, and to care about other chronic diseases of the same subjects.

2- Epidemiology: (4) discussion of cohort studies methodology for multiple measurements

in chronic diseases; (5) measurement issues in medication adherence and clinical inertia

research; (6) measuring health care quality, equity to health care access, and ethnicity as

a variable in epidemiological research;

In Portugal it is not common to have longitudinal prospective studies, particularly at the primary care level. These studies require a high level of organization and professional management, along with a high-motivated team who will create and maintain a strong commitment and relation with all participants and everyone else involved. We expect

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that, in the course of this study, we will be able to make collaborations with other researchers, so that we and other may take further scientific and clinical advantage with this effort. Therefore, we expect that new projects will be created from these opportunities. As we have additional preliminary results, we will be particularly interested in proposing and testing interventions aiming to improve high blood pressure control and anti-hypertensive adherence.

3- Immigrant’s health: (7) equity to health care access among immigrants and non-

immigrants; (8) discussion of the inclusion of ethnic minorities in health outcomes

research; (9) ethnic inequality in health status; (10) acculturation and health and

determinants for adherence in immigrants.

In Portugal there are few studies about migration and health and none about medication or control of a chronic disease in migrants. As far as we know, this will be the first longitudinal study with a prospective cohort of adult immigrants. A recent cohort study was conduct with children with the objective of defining the prevalence of immigrant children and to assess the children in their first months of life morbidity and mortality.41 We expect a better understand of changes in health related to migration status, which may lead to evidence-based measures regarding health services organization and specific intervention programs.

We expect, during the next 2-3 years, to publish about 2 to 4 papers per year (total of 9-10

papers), both at national and international peer-reviewed journals. We estimate a similar number

of presentations at national and international meetings. This research unit is responsible for the

Master Degree in Epidemiology at the Lisbon’s University Medical School. This project should

provide enough scientific material for 2 master theses. Therefore, we anticipate the opportunity

to interest students in project and to present, during the next 2-3 years, about 1 seminar per year

concerning this study.

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