Randomised, placebo-controlled trial (n=400) of the polypill in individuals at raised risk of cardiovascular disease

Introduction

Heart attack and stroke are leading causes of hospitalisation and early death worldwide. One of the most hotly debated research questions is whether a "polypill" (containing aspirin and medicines to lower blood pressure and cholesterol in one tablet) can really reduce these diseases by three-quarters or more. PILL Pilot will look at the effects of the polypill on blood pressure, cholesterol and tolerability. 400 people who are at increased risk of having a heart attack or stroke (due to a combination of factors such as age, sex, blood pressure, cholesterol and smoking) but who are not currently receiving treatment will be randomly assigned to receive the polypill or a placebo for 12 weeks. The trial involves researchers from Australia, Brazil, India, New Zealand, The Netherlands, UK and USA. The results will be used to plan a larger trial that will look at the risks and benefits of the polypill for the prevention of cardiovascular disease.

Rationale

One of the most hotly debated issues in cardiovascular disease (CVD) research currently is whether a "polypill" (a new combination cardiovascular medication containing aspirin and agents to lower blood pressure and cholesterol) can really reduce CVD by three-quarters or more. This pilot trial will assess the efficacy and tolerability of the polypill and provide preparatory data for a large clinical endpoint trial of the polypill in people at raised cardiovascular risk. The pilot trial will be undertaken by an international research network in Australia, Brazil, India, New Zealand, The Netherlands, UK and the USA.

Aims

To measure the efficacy (change in systolic blood pressure and LDL cholesterol) and tolerability of a polypill in individuals with raised risk of a cardiovascular event. Secondary aims are to measure adherence, the change in diastolic blood pressure, total cholesterol, HDL cholesterol, cholesterol:HDL cholesterol ration, non-HDL cholesterol and triglycerides, frequency of switching to open-label treatment, estimated CVD risk and adverse events.

Design

Participants will include those who have an absolute risk of a major cardiovascular event in the next 5 years of 7.5% or more, (based on the Framingham risk function and presence of other major cardiovascular risk factors) but who do not meet current guidelines for treatment with aspirin, or blood pressure-lowering or cholesterol-lowering medications. To be eligible, there must be no clear indication for, or contraindication to, the polypill components. Participants will be recruited using primary care screening, referrals and media advertisements. It is planned that 400 participants will be recruited - 100 from  India and 50 from each of Australia, Brazil, New Zealand, The Netherlands, UK and the USA. Eligible individuals will be randomised to 12 weeks treatment with the polypill (aspirin 75mg, simvastatin 20mg, lisinopril 10mg, hydrochlorothiazide 12.5mg) or to an identical matching placebo. Primary outcomes: Efficacy (change in systolic blood pressure, change in LDL cholesterol) and tolerability (the proportion who withdraw from trial treatment). Secondary outcomes: Treatment adherence (measured by self-reported and pill count), change in diastolic blood pressure, total cholesterol, HDL cholesterol, total cholesterol:HDL cholesterol ration, non-HDL cholesterol, triglycerides, frequency of switching to open-label treatment, change in CVD risk, and adverse events.

Study Status

This study is now complete and results are expected late 2011.

Funding

This study is funded by:

• Wellcome Trust
• Dr Reddy's Laboratories Limited - manufacture and supply of polypill and placebo

New Zealand:
Health Research Council of New Zealand (International Investment Opportunities Fund) - recruitment and follow-up of participants in New Zealand
The National Heart Foundation of New Zealand -  Research Fellow Fellowship for Natasha Rafter.

Australia:
National Health & Medical Research Council

UK:
British Heart Foundation.

Other sources of funding are being sought to enable recruitment and follow-up in other participating countries.

CTRU Investigators

Anthony Rodgers, Principal Investigator, Senior Research Fellow, now at The George Institute
Natasha Rafter, Research Fellow
Stephen Vander Hoorn, Senior Biostatistican


Project Manager
Angela Wadham

The CTRU secured funding from the Health Research Council of New Zealand International Investments Opportunity Fund. The study was designed in collaboration with the international investigators. CTRU staff are involved in the overall co-ordination of the project in their role as the International Coordinating Centre (ICC). Local Trial Management for New Zealand will be undertaken by the CTRU. Data Management for all participants will be undertaken by the CTRU and CTRU staff will undertake the main analyses.

Collaborators

Rod Jackson, Section of Epidemiology & Biostatistics, University of Auckland, New Zealand
Otavio Berwanger, Hospital do Coracao (Cardiac Hospital, Sao Paulo,  Brazil
Richard Grimm, Berman Center for Outcomes and Clinical Research, Minneapolis Medical Research Foundation, USA
Jim Neaton, Division of Biostatistics, University of Minnesota, USA
Bruce Neal,  Anushka Patel, The George Institute of International Health , University of Sydney, Australia
Neil Poulter,  Simon Thom, National Heart and Lung Institute, Imperial College, London, United Kingdom
Srinath Reddy, All India Institute for Medical Sciences, New Delhi, India
Rick Grobbee, Julius Center for Health Sciences and Primary Care University Medical Center, Utrecht, The Netherlands

Publications

PILL Collaborative Group. An international randomised placebo-controlled trial of a four-component combination pill (‘‘Polypill’’) in people with raised cardiovascular risk. PLoS ONE 2011; 6(5):e19857. doi:10.1371/journal.pone.0019857.