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Kanyini Polypill Trial

Cardiovascular disease (CVD) is Australia’s biggest killer and leading cause of loss of healthy life years. Aboriginal people experience a heavy burden of CVD.

Current Australian therapeutic guidelines recommend, on well-established evidence, long-term treatment of individuals at high cardiovascular risk with antiplatelet, blood pressure-lowering and cholesterol-lowering drugs. However, there is a large gap between recommendations and actual practice, and innovation is required to realise the full potential of these preventive treatments.

polypillFixed-dose combination therapy with a “polypill” represents a new way of providing these guideline-indicated medications and a major new opportunity to address this gap. It has been proposed that a polypill could improve adherence to recommended treatment by reducing the overall complexity of treatment for doctors and patients, and improve access by reducing costs.

The Kanyini polypill trial will rigorously test these assumptions. Improving access to effective cardiovascular medications has considerable potential to improve population health, and in particular, to help reduce inequities in healthcare access within the Australian population.

Study design

Open label, randomised, controlled trial (n=600) of the polypill compared to usual care for Aboriginal and Non-Aboriginal  people at high risk of cardiovascular disease.

Aims

To assess whether provision of a polypill (containing low dose aspirin, a statin and two blood pressure lowering medicines) compared to usual cardiovascular medications improves adherence and clinical outcomes in high-risk patients. Secondary aims are to measure prescription of combination therapy, barriers to adherence, quality of life, safety, cardiovascular events, renal events, prescriber acceptability, and healthcare resource consumption.

Patient recruitment

The study centres are the Aboriginal Community Controlled Health Services (ACCHS) participating in the Kanyini Vascular Collaboration and mainstream primary care services throughout New South Wales and Victoria. Participants at high risk of CVD have been recruited through these services. Risk is assessed using the adjusted Framingham risk assessment in accordance with the Australian National Heart Foundation and the New Zealand Guidelines Group. Based on this, inclusion criteria have been:

  1. Any person with established CVD (Ischaemic Heart Disease, Stroke/TIA or Peripheral Vascular Disease); or
  2. Any person with a calculated 5 year CVD risk of 15% or greater.

Five year CVD risk has been calculated based on the 1991 Anderson Framingham risk equation. In recognition of the potential for this equation to underestimate the actual risk in Indigenous people, a 5% risk increase has been added to the calculated risk as per the NZ guidelines recommendations.

Randomisation and study medication

Eligible participants have been randomised to up to 24 months treatment with the polypill or to continued usual care:

  • Polypill: Version 1 – aspirin 75mg, simvastatin 40mg, lisinopril 10mg, atenolol 50mg; version 2 – aspirin 75mg, simvastatin 40mg, lisinopril 10mg, hydrochlorothiazide 12.5mg. The choice of polypill is at the discretion of the prescribing general practitioner. The polypill will be supplied, and associated charges levied, in accordance with local ACCHS policy for medications.
  • Usual care: Separate cardiovascular preventive medications (eg. antiplatelet, blood pressure lowering and cholesterol lowering medicines) as prescribed by the ACCHS.

For both groups, any advice and /or other interventions relating to other preventive measures, including those relating to lifestyle modification, will continue at the discretion of the responsible clinician. Similarly all changes to medication in both groups will be at the discretion of the GP.

Data collection and follow-up

Basic Study Plan

Basic Study Plan

Participants will be followed up for an average of 18 months. Blood pressure and fasting lipids will be measured at baseline, and study completion. Self-reported adherence will be assessed at study visits and also via follow-up with Indigenous Research Fellows (IRFs) at 1, 6, and 18 months. IRFs will also ask about barriers to adherence, quality of life, cardiovascular and other serious adverse events, and symptoms causing withdrawal of cardiovascular medications. IRFs will meet with GPs at 12 months to evaluate prescriber acceptability of the prescribing strategy (polypill or usual care) for each participant and at the end of the study to assess overall acceptability for all their patients in the trial.

ACCHS records of primary care consultations, cardiovascular prescribing, and cardiovascular laboratory tests performed, plus where feasible electronic linkage to national datasets and patient reporting of cardiovascular specialist visits will contribute to an economic analysis.

Outcomes

  • Primary outcomes: Self-reported current use of antiplatelet, statin, and combination (= 2) blood pressure lowering therapy), change in blood pressure, change in LDL-cholesterol, at 2 years.
  • Secondary outcomes: Prescription of statin and (= 2) blood pressure lowering agents at two years, self-reported barriers to adherence, serious adverse events, cardiovascular events, renal events,symptoms causing withdrawal of cardiovascular medications, quality of life, prescriber acceptability, change in other lipid fractions (HDL-cholesterol, total cholesterol, triglycerides), and healthcare resource consumption.

Statistical power

Accounting for deaths and loss to follow-up, randomisation of 600 participants will provide 90% power at a two-sided 0.05 significance level to detect at least 4 mmHg difference in systolic blood pressure, and at least 0.25 mmol/L difference in total cholesterol. This assumes the standard deviation around the baseline for these variables is 14 mmHg and 0.9 mmol/L, respectively. With this number of participants there will be sufficient power to detect a 30% relative improvement in adherence (e.g. from a 50% adherence in usual care to 80% with the polypill)

Progress

Consultations with Kanyini collaboration partner sites regarding participation in the studyhave been completed and ethical approval has been granted by the relevant jurisdictions in NSW, Queensland, Central Australia and the Top End. The trial protocol is registered with the Australian and New Zealand Clinical Trials Registry: ACTRN12608000584336.

Recruitment commenced in early 2010, and as at March 2012 the Kanyini GAP study has been recruiting for 24 months and has more than 600 participants randomised. Recruitment has been challenging, but at each site, the team of GPs, Research Nurse/Coordinators and Indigenous Research Fellows are working together to achieve their recruitment targets. We now have over 80 GPs and Pharmacists on board committed to the study. The international sister studies are well under way. The UMPIRE study, being conducted in India and Europe, met its recruitment target of 2000 in July this year. The IMPACT study continues to recruit in New Zealand.

For further information regarding this project, please email Caroline Wu.