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Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care

BMJ 2014; 348 doi: (Published 27 May 2014) Cite this as: BMJ 2014;348:g3318
  1. Vanessa Selak, senior research fellow1,
  2. C Raina Elley, associate professor2,
  3. Chris Bullen, associate professor1,
  4. Sue Crengle, senior research fellow1,
  5. Angela Wadham, senior project manager1,
  6. Natasha Rafter, senior research fellow1,
  7. Varsha Parag, biostatistician1,
  8. Matire Harwood, senior lecturer3,
  9. Robert N Doughty, professor1,
  10. Bruce Arroll, professor2,
  11. Richard J Milne, associate professor4,
  12. Dale Bramley, chief executive officer5,
  13. Linda Bryant, honorary research fellow2,
  14. Rod Jackson, professor4,
  15. Anthony Rodgers, professor6
  1. 1National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand
  2. 2Department of General Practice and Primary Health Care, University of Auckland, Auckland, New Zealand
  3. 3Te Kupenga Hauora Māori, University of Auckland, Auckland, New Zealand
  4. 4Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand
  5. 5Waitemata District Health Board, Takapuna, Auckland, New Zealand
  6. 6The George Institute for Global Health, Sydney, NSW, Australia
  1. Correspondence to: V Selak v.selak{at}
  • Accepted 2 May 2014


Objective To evaluate whether provision of fixed dose combination treatment improves adherence and risk factor control compared with usual care of patients at high risk of cardiovascular disease in primary care.

Design Open label randomised control trial: IMPACT (IMProving Adherence using Combination Therapy).

Setting 54 general practices in the Auckland and Waikato regions of New Zealand, July 2010 to August 2013.

Participants 513 adults (including 257 indigenous Māori) at high risk of cardiovascular disease (established cardiovascular disease or five year risk ≥15%) who were recommended for treatment with antiplatelet, statin, and two or more blood pressure lowering drugs. 497 (97%) completed 12 months’ follow-up.

Interventions Participants were randomised to continued usual care or to fixed dose combination treatment (with two versions available: aspirin 75 mg, simvastatin 40 mg, and lisinopril 10 mg with either atenolol 50 mg or hydrochlorothiazide 12.5 mg). All drugs in both treatment arms were prescribed by their usual general practitioners and dispensed by local community pharmacists.

Main outcome measures Primary outcomes were self reported adherence to recommended drugs (antiplatelet, statin, and two or more blood pressure lowering agents) and mean change in blood pressure and low density lipoprotein cholesterol at 12 months.

Results Adherence to all four recommended drugs was greater among fixed dose combination than usual care participants at 12 months (81% v 46%; relative risk 1.75, 95% confidence interval 1.52 to 2.03, P<0.001; number needed to treat 2.9, 95% confidence interval 2.3 to 3.7). Adherence for each drug type at 12 months was high in both groups but especially in the fixed dose combination group: for antiplatelet treatment it was 93% fixed dose combination v 83% usual care (P<0.001), for statin 94% v 89% (P=0.06), for combination blood pressure lowering 89% v 59% (P<0.001), and for any blood pressure lowering 96% v 91% (P=0.02). Self reported adherence was highly concordant with dispensing data (dispensing of all four recommended drugs 79% fixed dose combination v 47% usual care, relative risk 1.67, 95% confidence interval 1.44 to 1.93, P<0.001). There was no statistically significant improvement in risk factor control between the fixed dose combination and usual care groups over 12 months: the difference in systolic blood pressure was −2.2 mm Hg (−4.5 v −2.3, 95% confidence interval −5.6 to 1.2, P=0.21), in diastolic blood pressure −1.2 mm Hg (−2.1 v −0.9, −3.2 to 0.8, P=0.22) and in low density lipoprotein cholesterol −0.05 mmol/L (−0.20 v −0.15, −0.17 to 0.08, P=0.46). The number of participants with cardiovascular events or serious adverse events was similar in both treatment groups (fixed dose combination 16 v usual care 18 (P=0.73), 99 v 93 (P=0.56), respectively). Fixed dose combination treatment was discontinued in 94 participants (37%). The most commonly reported reason for discontinuation was a side effect (54/75, 72%). Overall, 89% (227/256) of fixed dose combination participants’ general practitioners completed a post-trial survey, and the fixed dose combination strategy was rated as satisfactory or very satisfactory for starting treatment (206/227, 91%), blood pressure control (180/220, 82%), cholesterol control (170/218, 78%), tolerability (181/223, 81%), and prescribing according to local guidelines (185/219, 84%). When participants were asked at 12 months how easy they found taking their prescribed drugs, most responded very easy or easy (224/246, 91% fixed dose combination v 212/246, 86% usual care, P=0.09). At 12 months the change in other lipid fractions, difference in EuroQol-5D, and difference in barriers to adherence did not differ significantly between the treatment groups.

Conclusions Among this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high.

Trial registration Australian New Zealand Clinical Trial Registry ACTRN12606000067572.


  • We thank the trial participants; participating general practitioners; general practice staff; pharmacists; pharmacy staff; primary health organisations and their staff; the Endpoint Adjudication Committee: Kate Scott (chair), Ruvin Gabriel, and Neil Anderson; and the Health Research Council Data Safety Monitoring Board, particularly Katrina Sharples (chair) and Ralph Stewart (lead reviewer).

  • Trial protocol: Selak V, Elley CR, Crengle S, Harwood M, Doughty R, Arroll B, Bryant L, Rafter N, Vander Hoorn S, Wadham A, Wells S, Milne R, Jackson R, Bramley D, Rodgers A. Improving adherence using combination therapy (IMPACT): design and protocol of a randomised controlled trial in primary care. Contemp Clin Trials 2011;32:909-15.

  • IMPACT Steering Committee: CB (chair), SC (co-chair), BA, DB, LB, RND, CRE, MH, RJ, RJM, VP, NR, AR, VS, and AW.

  • Previous IMPACT Steering Committee members: Jennie Connor, Robert Cook, Valery Feigin, Tim Maling, Bruce Neal, Anushka Patel, Avinesh Pillai, David Simmons, and Stephen Vander Hoorn.

  • IMPACT research nurses: Anne Blundell, Denise Miller, Puti Nicholls, Anna Ruri, and Julia Thomson.

  • National Institute for Health Innovation Coordinating Centre: Stephen Boswell, Karen Carter, Mary Cosson, Lyndsay Cummings, Deanne Douglas, John Faatui, Shelia Fisher, Liz Glen, Yulong (Helen) Gu, Terry Holloway, Kate Hudson, Joy Jiang, Arier Lee, Jo Lorimer, Donovan Marshall, Jo Michie, Clark Mills, Colleen Ng, Rina Prasad, Tamsin Scott, Johan Strydom, Sonia Van Gessel, and Puti Wilson.

  • GP investigators: Harley Aish, Nasim Ali, John Allen, Mark Arbuckle, Bruce Arroll, David Blumberg, Mary Buckler, Vispi Buhariwalla, Lorna Buhler, David Bulmer, Len Brake, Simon Chong, Karl Cole, Peter Coleman, Denise Dalziel, Richard Davies, Anjana de Almeida, David De Lacey, Alison Denyer, Kalawati Deva, Mutthuvel Devarajah, Rajendra Dhana, Chris Dickey, Peter Didsbury, Gamini Ediriweera, Raina Elley, Kazi Ely, Katherine Farmer, Roshan Fernandes, Tana Fishman, Lisa Fuller, Pramod Galgali, Maryanne Gane, Adrian Gane, John Gates, Julia Gault, Soshamma George, Shobi Gopal, Christopher Gross, Peter Guy, Tangimoana Habib, J A Hanne, David Hoadley, Douglas Horne, Timothy Hou, Gail Houng-Lee, Neil Hefford, Nizmal Islam, Stephen Joe, Nathan Joseph, Greg Judkins, Oruba Khalil, Katrina Kirikino, James Kriechbaum, Siobhan Latham, Diane Leach, Quoa Young Lee, Gavin Lobo, Chong Lee Loh, Malcolm Lowe, Himali McInnes, Michael Morrison, Margaret Muir, Chris Naughton, Bala Newton, Martin Ng, Paul Nola, Bhavana Patel, Shahnaz Perveen, William Reyneke, Richard Ruddell, Pravedh Sewnarain, David Shand, Michael Slatter, Benjamin Soe, Rob Stewart, Carolyn Sutton, Tony Svenson, Antony Taylor, James Te Whare, Reesa Thomas, John Upsdell, Raj Varma, Rama Velalagan, Iain Wakefield, Marcia Walker, Jeremy West, Tim Wilkinson, Mike Williams, Victor Wong, and Peter Woolford.

  • Pharmacies: Avondale Medical Pharmacy, Avondale Pharmacy, Barry Roberts Chemist Huntly, Clendon Pharmacy, Coxs Pharmacy Glen Innes, Dawson Road Pharmacy East Tamaki, Elstree Pharmacy Glen Innes, Family Care 7 Day Pharmacy Otara, Graeme Angus Pharmacy Papatoetoe, Graeme Avenue Pharmacy Mangere East, Greenbay Pharmacy, Gopals Pharmacy Grey Lynn, Hamilton East Pharmacy, Healthcare Pharmacy Clendon, Herne Bay Pharmacy, Hillpark Care Centre Manurewa, John Hogg Pharmacy Mangere, Johnsons Pharmacy Otara, Leabank Pharmacy Manurewa, Life Pharmacy Manukau, McLaren Park Pharmacy Henderson, Mangere Pharmacy, Mangere Healthcare Pharmacy, Manurewa Medical Centre Pharmacy, Medi-Centre Pharmacy Henderson, Mt Smart Pharmacy Onehunga, New Lynn West Pharmacy, Ngaruawahia Pharmacy, Onehunga Centre Pharmacy, Otara Community Pharmacy, Papakura Marae Pharmacy, Papatoetoe City Centre Pharmacy, Peter Boles Pharmacy Manurewa, Panmure Pharmacy, Pharmacy 44 Ltd Rotorua, Ranui Pharmacy, Roberts Ngaruawahia Pharmacy, Seddon Street Pharmacy Pukekohe, Southmall Pharmacy Manurewa, Te Kohao Health Nga Hua Pharmacy Hamilton, Thorntons Pharmacy Avondale, Tuakau Amcal Pharmacy, Turuki Pharmacy Mangere, Unichem Guys Pharmacy Papakura, Unichem Pharmacy Manurewa, Waiuku Medical Pharmacy, and Westview Care Chemist Glen Eden.

  • Contributors: AR and NR had the initial idea for the trial. The trial was initially designed by AR, NR, BA, DB, Jennie Connor, Robert Cook, SC, RND, Valery Feigin, RJ, Tim Maling, RM, Bruce Neal, Anushka Patel, David Simmons, and Stephen Vander Hoorn. Additional contributions to trial design were made by VS, CRE, AW, and MH. The statistical analysis plan was written by Stephen Vander Hoorn, AR, and CRE. The trial was implemented by AW, VS, CRE, SC, MH, CB, Avinesh Pillai, and NR. Data collection tools were initially designed by VS, NR, AR, SC, Valery Feigin, Stephen Vander Hoorn, and Andrew Jull. Additional contributions to the design of data collection tools were made by CRE, MH, and AW. AW, VS, CRE, Avinesh Pillai, and CB monitored data collection. VP and VS analysed the data. VS wrote the first draft of the paper. AR and CRE made substantial contributions to revisions. All coauthors reviewed and provided feedback on the paper. CB is guarantor for the paper.

  • Funders: The trial was funded by project grants from: New Zealand Health Research Council (06/582, 12/889), National Heart Foundation of New Zealand (1376), New Zealand Lotteries Grants Board (230904-310308), the Elsie Shrimpton Fund (University of Auckland), PHARMAC (New Zealand’s Pharmaceutical Management Agency; A499735-QA24208), Te Kupenga Hauora Māori (University of Auckland), Auckland regional district health boards (Auckland, Counties Manukau, and Waitemata; 12/889), the Faculty Research Development Fund (University of Auckland), and the Auckland Medical Research Foundation. VS (1384) and NR (1156) received National Heart Foundation of New Zealand research fellowships while working on the trial. DRL (Hyderabad, India) provided free of charge the fixed dose combination treatment for use in the trial. The George Institute for Global Health (employer of AR) received a grant from DRL for the SPACE collaboration coordinating centre ( which provides academic and administrative support to achieve collaboration between this and two other clinical trials involving fixed dose combination treatment provided by DRL free of charge. Researcher independence and access to data: None of the trial sponsor, funders or DRL had any role in study design; the collection, analysis, or interpretation of data; the writing of the article; or the decision to submit the article for publication. All authors are independent from trial funders. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: Support for the submitted work: project grants from the New Zealand Health Research Council, the National Heart Foundation of New Zealand, the New Zealand Lotteries Grants Board, the Elsie Shrimpton Fund (University of Auckland), PHARMAC (New Zealand’s Pharmaceutical Management Agency), Te Kupenga Hauora Māori (University of Auckland), Auckland regional district health boards (Auckland, Counties Manukau, and Waitemata), the Faculty Research Development Fund (University of Auckland), and the Auckland Medical Research Foundation. The Health Research Council was the trial sponsor. VS is, and NR was, a National Heart Foundation of New Zealand research fellow. AR was a National Heart Foundation of New Zealand senior fellow during the course of the trial. The George Institute for Global Health (employer of AR) has received a grant from Dr Reddy’s Laboratories Limited (DRL), Hyderabad, India for the SPACE collaboration coordinating centre (, which provides academic and administrative support to achieve collaboration between this and two other clinical trials involving fixed dose combination treatment provided by DRL free of charge. RND holds the New Zealand Heart Foundation chair of heart health. No financial relationships with any organisations that might have an interest in the submitted work in the previous three years. Other relationships or activities that could appear to have influenced the submitted work: The George Institute for Global Health (employer of AR) recently secured an exclusive global license for the fixed dose combination treatment used in this trial after a decision by DRL not to proceed with taking the products to market because of existing regulatory requirements. VS, CRE, AW, NR, and AR received reimbursements for travel and accommodation from DRL to attend international collaborative meetings on fixed dose combination treatment, but have no financial interest in this product. VS received reimbursement for travel from the George Institute for Global Health to attend an international collaborative meeting on fixed dose combination treatment. NR received reimbursement for travel from the George Institute for Global Health. MH is on the board of directors for the Health Research Council of New Zealand. BA is on the educational committee for PHARMAC (New Zealand’s Pharmaceutical Management Agency) and its anti-infective agent advisory board. BA was on the primary care advisory board for the Future Forum from 2003 to 2008. This forum is funded by Astra-Zeneca (UK). DB is employed by the Waitemata District Health Board, which, along with other district health boards, contributed funding.

  • Ethical approval: The trial was conducted in accordance with the code of ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Ethical approval of the trial protocol and participant information documents was obtained from the New Zealand Northern X Regional Ethics Committee (NTX/06/06/072). Trial participants gave informed consent before taking part.

  • Data sharing: The IMPACT Steering Committee supports the policy of making relevant anonymised patient level data available on reasonable request. Requests should be directed via the principal investigator, CB (c.bullen{at}

  • Transparency: CB affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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