title: 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.
abstract: 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.
  
  
  METHODS
  Open label randomised control trial: IMPACT (IMProving Adherence using Combination Therapy).
  
  
  METHODS
  54 general practices in the Auckland and Waikato regions of New Zealand, July 2010 to August 2013.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trial Registry ACTRN12606000067572.
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand v.selak@auckland.ac.nz.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Selak
authors.affiliation: Department of General Practice and Primary Health Care, University of Auckland, Auckland, New Zealand.
authors.forename: C Raina
authors.initials: CR
authors.lastname: Elley
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Chris
authors.initials: C
authors.lastname: Bullen
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Sue
authors.initials: S
authors.lastname: Crengle
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Angela
authors.initials: A
authors.lastname: Wadham
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rafter
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Varsha
authors.initials: V
authors.lastname: Parag
authors.affiliation: Te Kupenga Hauora Māori, University of Auckland, Auckland, New Zealand.
authors.forename: Matire
authors.initials: M
authors.lastname: Harwood
authors.affiliation: National Institute for Health Innovation, University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Doughty
authors.affiliation: Department of General Practice and Primary Health Care, University of Auckland, Auckland, New Zealand.
authors.forename: Bruce
authors.initials: B
authors.lastname: Arroll
authors.affiliation: Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Milne
authors.affiliation: Waitemata District Health Board, Takapuna, Auckland, New Zealand.
authors.forename: Dale
authors.initials: D
authors.lastname: Bramley
authors.affiliation: Department of General Practice and Primary Health Care, University of Auckland, Auckland, New Zealand.
authors.forename: Linda
authors.initials: L
authors.lastname: Bryant
authors.affiliation: Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.
authors.forename: Rod
authors.initials: R
authors.lastname: Jackson
authors.affiliation: The George Institute for Global Health, Sydney, NSW, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rodgers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001262:Atenolol; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D008078:Cholesterol, LDL / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D017706:Lisinopril; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D011320:Primary Health Care / Q000706:statistics & numerical data; D012044:Regression Analysis; D012307:Risk Factors; D019821:Simvastatin; D055815:Young Adult; D016903:Drug Monitoring
chemical_list: D000959:Antihypertensive Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006852:Hydrochlorothiazide; D001262:Atenolol; D019821:Simvastatin; D017706:Lisinopril