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ImProving Adherence using Combination Therapy (IMPACT) randomised controlled trial: Methods
Introduction
Although the polypill has been shown to improve adherence, its effect on blood pressure and cholesterol has been inconsistent when compared with usual care and there is only a relatively small evidence base from which to assess its safety among people with indications. A New Zealand randomised controlled trial could provide clarity on the potential role of a polypill in enhancing the implementation of guideline-recommended therapy in this country by providing local evidence. In addition, a trial could expand the international evidence base regarding the effect of polypill-based compared with usual care on blood pressure and cholesterol, as well as safety. Such a trial was conducted, the IMProving Adherence using Combination Therapy (IMPACT) trial, and forms the second part of this thesis. This chapter describes the methods of the IMPACT trial. The aims and hypotheses of the IMPACT trial are presented first. The design of the trial is described with sections on the trial population, sample size, randomisation, allocation concealment, the intervention and control, blinding, outcomes, data collection, analyses and trial governance and management. Trial processes are described including training, recruitment, baseline and follow-up assessments and pharmacovigilance. The rationale for key design elements is then provided, ending with a particular emphasis on the way in which the trial implemented an indigenous right-based perspective.
Aims and hypotheses
The aims of the trial were to investigate the following: Does polypill-based care increase the proportion of people at high risk of cardiovascular disease who are adherent to guideline-recommended medication over a one-year period, compared with usual care? Does polypill-based care reduce blood pressure and low density lipoprotein cholesterol in people at high risk of cardiovascular disease over a one-year period, compared with usual care?
The hypotheses of the trial were that, compared with usual care: A greater proportion of people at high risk of cardiovascular disease receiving polypillbased care are adherent to guideline-recommended medication over a one-year period.The reduction in blood pressure and low density lipoprotein cholesterol is greater in people at high risk of cardiovascular disease receiving polypill-based care over a one-year period.
Design
IMPACT was an open-label, parallel, randomised controlled trial (Figure 11). The trial sought to randomise equal numbers of Māori and non-Māori to polypill-based care or usual care. Follow-up for each participant was to continue until 12 months after the last participant had been randomised.
Primary Health Organisation
Primary Health Organisations are groups of providers working with their communities to improve health and reduce health inequalities by coordinating and providing essential primary health care services, including general practice services, to an enrolled population in New Zealand. Primary Health Organisations were eligible for inclusion in the trial if they met ALL of the following criteria:
Located within the Auckland or Waikato regions of New Zealand
Likely to have high enrolment of Māori
Primary Health Organisations were sought that were Māori-led, had a large enrolled population or that were located within an area in which a high proportion of Māori resided.
The trial aimed to randomise equal numbers of Māori and non-Māori so that information about Māori would be obtained to at least the same depth and breadth as that obtained for non-Māori. This meant oversampling of Māori who comprise just 15% of the total New Zealand population.[32]
Endorsed the IMPACT trial
Supported the IMPACT trial team approaching general practices affiliated with the Primary Health Organisation
General practices and general practitioners
General practices were eligible for inclusion in the trial if they met ALL of the following criteria:
Affiliated with an eligible Primary Health Organisation
Had practice electronic records accessible to trial staff
Had the capacity for at least one general practitioner to participate in the trial
General practitioners were eligible for inclusion in the trial if they met ALL of the following criteria:
Working (either part-time or full-time) at a participating general practice
Had completed training on the trial and trial procedures
Agreed to abide by the trial protocol
Were willing to prescribe the polypill to participants randomised to polypill-based care and to notify trial staff of any serious adverse events in any trial participant
Had signed a contract regarding their responsibilities on the trial
Pharmacies
Pharmacies were eligible for inclusion in the trial if they met ALL of the following criteria:
At least one pharmacist in the pharmacy had completed training on the trial and trial procedures
Agreed to abide by the trial protocol
Agreed to stock the polypill and store it at <25°C
Were willing to dispense the polypill only to participants randomised to polypill-based care (according to their trial identification card) and on receipt of a prescription for the polypill
Had signed a contract regarding their responsibilities on the trial
Participants
Patients were eligible for inclusion in the trial if they met ALL of the following criteria.
Were aged 18-79 years
Were at high risk of cardiovascular disease (as defined in Table 27)
Their usual general practitioner considered that all of the medications in at least one of two polypills available for the trial were indicated for them
Their usual general practitioner was uncertain as to whether therapy would be best provided as a polypill or with usual care (i.e. ‘clinical equipoise’, see below)
Were able to give informed consent
The definition of ‘high risk’ of cardiovascular disease (Table 27) was based on New Zealand cardiovascular guidelines from 2003.[36] These were the most up to date guidelines when the trial was initially designed and electronic case record forms with an integrated cardiovascular risk calculator developed, in 2006. The guidelines were updated in 2009,[39] just prior to the initiation of trial recruitment. The definition used in the IMPACT trial is largely consistent with the 2009 update with some minor exceptions. For example, the trial definition includes metabolic syndrome as an adjustment factor in line with 2003 guidelines, whereas this was dropped in the 2009 update.
Sample size
The trial statistician estimated that 600 participants would provide 95% power at 2p = 0.05 to detect a 0.25 mmol/L difference in low density lipoprotein cholesterol and 4 mm Hg difference in systolic blood pressure between the intervention and control groups, assuming standard deviations around the change from baseline score of 0.8 mmol/L and 14 mm Hg respectively. This would also provide over 95% power to detect a 30% relative improvement in adherence (e.g. from 50% to 65% adherence). The recruitment target was revised down to 500 participants given available funding resources, which provided 89-93% power to detect the same risk factor differences and 92% power to detect a 30% relative improvement in adherence (see rationale for reduction in sample size ). Recruitment of equal numbers of Māori and non-Māori was planned to assess the consistency of effects across these group (rationale for equal recruitment provided ).
Randomisation and allocation concealment
Participants were randomised to either polypill-based care or usual care (1:1). Randomisation was activated by the general practitioner via the trial website. As randomisation was performed by a centralised online system, participants, general practitioners and trial staff had no way of knowing in advance whether a particular participant would be allocated to polypillbased or usual care. Likewise, participants, general practitioners and trial staff had no way of influencing allocation to polypill-based or usual care during the randomisation process. Randomisation used a minimisation algorithm with the following factors: Primary Health Organisation, history of cardiovascular disease (yes/no), level of baseline medication adherence (whether or not the participant self-reported current use of antiplatelet, statin and combination [≥ 2] blood pressure lowering agents) and ethnicity (Māori/non-Māori). As each successive patient was randomised, the minimisation algorithm calculated any imbalance within each of these factors. The probability that the patient was allocated to the treatment group with the lowest count was 0.9. This meant that the randomisation process minimised any imbalances between the numbers of patients in each treatment group (i.e. polypill vs usual care) according to Primary Health Organisation, history of cardiovascular disease, baseline medication adherence and ethnicity.
1. Introduction
1.1. Rationale
1.2. Aim and objectives
1.3. Contributions and funding
1.4. Structure of the thesis
2. Literature review
2.1. Introduction
2.2. Cardiovascular disease: importance, prevention, guidelines and implementation
2.3. Effectiveness and safety of aspirin for the primary prevention of cardiovascular disease
2.4. Effectiveness of aspirin for the primary prevention of cancer
2.5. Effectiveness and safety of a cardiovascular polypill
2.6. Summary
3. Systematic review and modelling of benefits and harms of aspirin in the primary prevention of cardiovascular disease
3.1. Introduction
3.2. Systematic review
3.3. Modelling
3.4. Summary
4. IMProving Adherence using Combination Therapy (IMPACT) randomised controlled trial: Methods
4.1. Introduction
4.2. Aims and hypotheses
4.3. Design
4.4. Statistical analyses
4.5. Registration and approvals
4.6. Governance, management and committees
4.7. Processes
4.8. Rationale for key design elements
4.9. Implementing an indigenous right-based perspective
4.10. Summary
5. IMProving Adherence using Combination Therapy (IMPACT) randomised controlled trial: Results
5.1. Introduction
5.2. Trial timeline
5.3. Participant recruitment and retention
5.4. Baseline characteristics
5.5. Primary outcomes
5.6. Secondary outcomes
5.7. Other outcomes
5.8. Summary
6. IMProving Adherence using Combination Therapy (IMPACT) randomised controlled trial: Discussion
6.1. Introduction
6.2. Summary of key findings
6.3. Trial strengths and limitations
6.4. Comparison with literature
6.5. Summary
7. Thesis conclusions
7.1. Rationale of the thesis
7.2. Objectives of the thesis
7.3. Summary of key findings of the thesis
7.4. Implications of the thesis
7.5. Unanswered questions and future research
7.6. Summary
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Effectiveness and safety of a cardiovascular polypill containing aspirin
