Burden of CVD in Pakistan

The WHO report on Global atlas on cardiovascular disease prevention and control states that cardiovascular diseases (CVDs) are the leading causes of death and disability in the world. Over 80% of CVD deaths take place in low-and middle-income countries [1]. Despite convincing evidence that lowering of blood pressure decreases cardiovascular morbidity and mortality, the control of hypertension has been poor in developing countries due to a multitude of reasons.

According to National Health Survey Pakistan (NHSP) hypertension was shown to affect 18% of adults aged >15 years and around 33% of adults above 45 years [2]. In Pakistan there is a lack of adequate data on the CVD disease burden as well as the risk factors involved.

Urban health and facilities available

A study done in urban settings (by Jafari et al.) found that 27.6%and 39.3% of hypertensive patients suffer from concomitant diabetes and hypercholesterolemia respectively, whereas 45.3% are smokers [3].

In urban areas, the availability and quality of the first level care public facilities is not adequate. This makes private clinics/ small hospitals an alternate “choice” for the first level care in urban areas. However, in the absence of a regulatory and/or partnership mechanism, the care delivery practices vary widely.

Public–private mix models in Pakistan

In Pakistan two main models of public-private mix (PPM) emerged so far are the “social franchise” and the “district-led partnership” models. The variants of social franchise model (e.g. greenstar, MSS model) have been tested and found workable for delivering reproductive health and communicable disease care interventions in selected urban areas.

The district-led partnership model has been developed through an extensive and systematic exercise in Pakistan. The exercise included: a) strategic framework and intervention design; b) guidelines and products for planning, implementing and monitoring partnership interventions; c) piloting and evaluation of guidelines and products; and d) scaling-up of the refined model^a for TB, malaria, and more recently MDR-TB interventions.

Involvement of the association

The Association is a not for profit company with vast experience of working in TB, lung health, reproductive health and cardiovascular diseases. The Association and Nuffield Institute have been the lead program technical partners for developing the district-led partnership model in Pakistan. Currently, the Association is responsible for implementing public-private partnership interventions in: 18 districts for DOTS and MDR-TB (TGF R-9), and 2 districts for RBM (TGF Round 7 and 10). This valuable experience and strong field presence will help the Association to implement the proposed CVD-HTN intervention in 1-2 of the districts with an ongoing public-private partnership for communicable disease control.

Rationale

The proposed implementation research is to develop and evaluate a model of delivering CVD-HTN care package through a network of private clinics, already engaged in communicable disease control activities. The care delivery dimensions that need further attention include: chronicity of disease requiring relatively long-term liaison between patient and care provider, higher prevalence, combination of drugs and lifestyle interventions, and poorly defined management support arrangements at district level.

The CVD-HTN care delivery modalities and products are required for ensuring quality and planning expansion. The proposed exercise is to develop and evaluate an intervention for delivering quality CVD-HTN care through enabled private health facilities. The set of implementation products may include: case management desk guide, training module, recording/reporting and monitoring instruments, and communication tool. These products will cover the technical and operational aspects of managing cases i.e. screening, diagnosis, prescription, education, follow-up etc.

Aim

The aim is to enhance the delivery of quality CVD-HTN care through private health facilities in urban settings. The conditions to be covered in the care package include: hypertension, type 2 diabetes, and hypercholesteremia.

Primary objective

To compare the mean change in systolic blood pressure (10 mmHg) in adult patients (>25 years) receiving enhanced CVD-HTN care package with the mean change in systolic blood pressure (5 mmHg) for those receiving routine care at the private facilities in Punjab.

Secondary objectives

Research question

The control of selected cardiovascular diseases will be assessed by measuring change in blood pressure, blood glucose, and serum cholesterol.

Hypothesis

Study design

A pragmatic parallel arms cluster randomized controlled trial (c RCT) with two arms will be conducted from January 2012 to December 2016 with a duration of 60 months.

The proposed cluster randomized controlled trial will evaluate the effects of delivering quality HTN-CVD care, through enabled private health care facilities, to achieve better adherence and hypertension control also blood glucose and serum cholesterol control. The trial will have two arms (Figure 1).

Interventions

Study setting

Sargodha is the tentatively proposed district for implementing the research. About one-third of the district population lives in urban areas (i.e. 1 million out of 3.1 million). About 38% of the urban population is above 25 years of age (i.e. 380,000), and about a quarter of these are expected to be hypertensives (95,000).

In Sargodha, the Association has actively been engaged in supporting the implementation of various disease control interventions through district health systems. These include communicable diseases like TB-DOTS and sexually transmitted infection (STI) control, tobacco cessation, public-private partnership, advocacy-communication and social mobilization for disease control, drug management enhancement etc. This experience-based understanding and trust with the district health office would help partners to implement the proposed public-private partnership innovation.

Study population

In these two districts, 12 private health facilities will be selected into the trial.

Data management procedures

Most of the data will be collected as a part of the care delivery process by doctors and paramedics on the ‘CVD card’. Other data related especially to trial will be recorded on the ‘trial registration form (TRF). Research assistant (RA) will visit the identified Lab on monthly basis and will collect test results. RA will visit each centre on monthly basis and will i) check each TRF for completeness and correctness, and those found with missing data will be acted upon accordingly. ii) correlate the Lab results with entries on TRF iii) check for drugs and supplies and reimburse for gaps. RA will send a copy of TRF and Lab test results to the central office i) at test one i.e. baseline ii) at test two i.e. final outcome, for data entry, cleaning and analysis.

Statistical considerations

Phases of the trial

The trial will have the following three phases: Refer to Figure 2.

1. 1)

   Inception & piloting phase. The main purpose of the two-year phase is to develop, pilot and refine the care delivery guidelines/ materials and trial design/ protocols before embarking upon the trial registration.

    

• The piloting experiences and results will enable the research team to:

• Assess the feasibility and acceptability, and then accordingly modifythe process for health facility selection (i.e. facility assessment, providers’ and communal consent for the trial etc.) and management support (logistic supplement, reporting, monitoring etc.)

• Assess the feasibility and acceptability, and then accordingly modifythe case management guidelines i.e. diagnosis, treatment, record keeping, follow-up etc.

• Assess the feasibility and robustness of the research protocols, then accordingly modify, the protocols for case inclusion/ exclusion, recruitment rate, and periodic assessment (research related).

• Revisit the assumed proportion of diabetics, dyslipidemic and smoker patients among adult hypertensive patients in local context.

• Revisit the assumptions about sample size calculation to meet the power of the study such as mean change (± standard deviation) in systolic blood pressure, glycaemic and cholesterol control, and tobacco cessation between intervention and control arms.

• Assess and modify, if needed, the proposed statistical methods to analyze the trial data.

• The qualitative interviews with providers (± patients) for assessing the feasibility during the trial piloting will also be adapted subsequently for the trial assessment. In short the trial piloting will inform the decision to implement the trial to get optimal results and valid evidence.

1. 2)

   Trial Implementation phase

    

• In the first 03 months of the trial implementation phase, the following arrangements will be made before start registering cases in the trial.

• Refine the case management guidelines/ materials Assess and shortlist the health facilities for possible inclusion in the trial. Randomization :The ASD central trial unit, under the supervision of Trial Steering Committee, will then randomize the facilities into two trial arms. Randomization preformed will be simple randomization. Each participating facility (cluster) will be given a unique ID which the investigators will be blinded to.12 different sheets of paper will be taken and the unique ID of each cluster will be written on the paper, which will be folded and sealed into an envelop.12 such sealed envelopes will be made. Then by a simple procedure, 6 sealed envelopes will be selected by hand picking them randomly from the pile of 12 sealed envelopes.6 will be hand picked for the intervention arm and 6 sealed envelopes for the control arm. The Steering committee will consist of a director, two people from ASD and two people from in-country (PMRC) and international partners (WHO).

• At least two doctors and two paramedics from each participating facility will be trained. The intervention facility staff will be trained on enhanced case management guidelines and materials including recording reporting and enhanced follow-up and referral, whereas the control facility staff will be trained only to register and report, use patient education brochure, and access HbA1c and cholesterol testing for trial patients.

• In the next 06 months of the trial implementation phase, the patients will be registered and enrolled in the trial, as per agreed protocols. During the period the baseline hypertension measurement will be validated by an external expert examination, kept blind to the trial arm as well as any previous measurements.

• The case management enhancement in the intervention arm will include: case management desk-guide for patient care, flip chart and brochure for patient education, mobile link for late patient retrieval, referral for advanced care (if needed), regular monitoring and support.

• Once the required number of trial patients is enrolled in the trial, the subsequent patients will receive HTN-CVD and associated care from the respective facility (as per prevailing case management protocols i.e. either intervention or control) but their results will not be included in the trial evaluation.

• The research team will closely monitor the inclusion and exclusion of trial patients, mainly to identify and respond to any deviation from the research protocols and/or case management processes.

• In the next 15 months of the trial implementation phase, the registered trial patients will be followed-up to measure the outcomes.

• All patients will pay for the case management services, as per facility protocols. However, the measurement of hypertension, HbA1c, serum cholesterol and carbon mono oxide in exhaled air will be paid from the project sources (as these measurements are being made solely for the trial evaluation). The referral to district headquarter hospital, as required, for specialist consultation (e.g. cardiology, ophthalmic examination, renal assessment, drug side effect) will be managed as per agreed guidelines for intervention arm and as per current routine in the control arm. The specialist facility will be encouraged to refer back patients to the respective referring facility, after providing the requested specialist care.

• The case management record on each patient will be maintained in the chronic disease register (to be developed and introduced through the trial inputs). The chronic disease register at each facility will provide the data for detailed analysis on case management experiences in the two trial arms.

• The modalities for periodically monitoring the participating facilities (including reviewing records and collecting reports) will be developed during the initial development phase (see section 12 below). The research team will ensure that each participating facility is monitored as per guidelines agreed for the respective facility (i.e. intervention and control).

• The research team will also supplement the logistic inputs at the participating facilities. This includes maintenance of BP apparatus, glucometer and supplies, print materials etc. at the participating facilities.

1. 3)

   Intervention Evaluation and Research Take-up phase

    

Current situation

Due to the high burden of disease where 1 in 3 individuals aged above 45 suffers from hypertension, topped with the fact that there is a dearth of a set of available, standardised guidelines for management, the disease is constantly on a hike in Pakistan. The government has made no effort to issue a set of guidelines adapted specifically for our population and this becomes more of a problem when managing CVD in urban population through private practitioners whose practices vary widely. If our set of context sensitive guidelines show an effectiveness in the proposed intervention districts, the 6 facilities in control arm will also be enabled for implementing the enhanced HTN-CVD care guidelines and materials. The enabling primarily will include staff training, guidelines and materials and monitoring support. Consultation with selected provincial health department staff will be conducted for their considering and planning (if possible) the scaling-up of HTN-CVD PPM intervention in other 31 districts of Punjab where PPM for communicable disease (TB) control is already being implemented through GFATM grant.

Addressing bias, error and limitations

Comparing the socio-demographic and health services profiles of the private facilities does not indicate any significant difference that can potentially lead to differences in care seeking behavior and/or quality of service. The proposed cluster randomization is expected to address the potential selection bias across the two trial arms.

The process of equal screening and diagnosing training in both arms will lead to similar disease intensity patients being recruited in both arms. Although similar training of health professionals in both arms in regards to better screening this will eliminate selection bias, it will lead to a inability to measure ‘case detection rate’ due to better screening.

The lack of masking (blinding) could introduce bias through two routes i.e. “incorrect measurement” and “leakage” from one group to another. There was a possibility of incorrect measurement of “blood pressure outcomes” by the facility doctor, who is aware of the intervention allocation. This possibility of measurement bias will be reduced through an unrelated external BP monitoring doctor who is unaware of the intervention allocation. Contamination across clusters is prevented by keeping a minimum distance between clusters.

The proposed randomization does not allow asking and responding to individual patient preferences. So the trial will not answer the question what would happen if health services are able to offer intervention according to individually tailored patient needs/ convenience. Further work will be needed to test the approaches sensitive to individual preferences, in the local programme setting.

The proposed method of randomization, ie concealed simple randomization has its own limitations. This method does not address the balance of baseline covariates. An alternative approach could have been addresses the need to control and balance the influence of covariates by using stratified randomization. This method can be used to achieve balance among groups in terms of baseline characteristics (covariates) of health facilities based on socio demographics of catchment population they feed into, size of health facility, patient load etc. Different strata /blocks of health facilities may have been made and then simple randomization done in each strata to achieve a balance of covarites. This could have minimized the biased that simple randomization does not address.

Ethical considerations

The proposed study design, i.e. a randomized controlled trial, is considered best for a prospective comparison of two or more options or interventions. The relevant details (e.g. selection of study and control population, sampling technique and sample size, statistical methods etc.) have carefully been considered to ensure valid measurements.

The endorsement of EDO (H), after explaining the trial significance and methods, will be obtained. Then a survey of eligible private health facilities will form the basis for selection of well functioning and willing to participate health facilities (i.e. consent to participate in the trial). At each selected health facility communal consent (from the respective catchment population) will be obtained, by inviting an agreed group of key community leaders. The facilities where communities consent to participate will then be randomized into two trial arms. The proposed process for seeking consent from the private providers and respective communities is considered ethical for the proposed cluster randomised controlled trial.

The selection of current practice as a control arm is also considered ethically acceptable. As there is no existing evidence for an association between the proposed interventions and better outcomes, the cluster randomization into trial arms is considered justified. No participant will be subjected to an additional burden or a potentially coercive influence, or deprived of any care that he/she would ordinarily receive. The outcome measurement will be based on an objective and quality assured data, gathered during the care delivery process. There are no apparent issues related with confidentiality of information about individual client in the trial.

The University of Leeds Research Ethics Committee, granted the trial ethical approval on 20 March 2012, ref: HSLTLM11026. National Bioethics Committee (NBC) Pakistan has granted ethical approval for the proposed project on 30 April 2012, ref: NBC:89 The trial has also been registered with the Current Controlled Trials ISRCTN34381594.