Statistical analysis plan for management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: the SingHypertension pragmatic cluster randomized controlled trial

INTRODUCTION: Cardiovascular disease (O'Lone E, Viecelli AK, Craig JC, Tong A, Sautenet B, Herrington WG, et al., Am J Kidney Dis 76(1):109-20, 2020) remains the leading cause of death in Singapore. Uncontrolled hypertension confers the highest attributable risk of CVD and remains a significant public health issue with sub-optimal blood pressure (BP) control rates. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of a multicomponent intervention (MCI) versus usual care on lowering BP among adults with uncontrolled hypertension visiting primary care clinics in Singapore. This article describes the statistical analysis plan for the primary and secondary objectives related to intervention effectiveness. METHODS: The study is a cluster randomized trial enrolling 1000 participants with uncontrolled hypertension aged ≥ 40 years from eight primary care clinics in Singapore. The unit of randomization is the clinic, with eight clusters (clinics) randomized in a 1:1 ratio to either MCI or usual care. All participants will be assessed at baseline, 12 months, and 24 months with measurements of systolic and diastolic BP, antihypertensive and statin medication use, medication adherence, physical activity level, anthropometric parameters, smoking status, and dietary habits. The primary objective of this study is to assess the effectiveness of MCI versus usual care on mean SBP at the 2-year follow-up. The primary outcome is SBP at 24 months. SBP at baseline, 12, and 24 months will be modeled at the subject level using a likelihood-based, linear mixed-effects model repeated measures (MMRM) analysis with treatment group and follow-up as fixed effects, random cluster (clinic) effects, Gaussian error distribution, and adjustment to degrees of freedom using the Satterthwaite approximation. Secondary outcomes will be analyzed using a similar modeling approach incorporating generalized techniques appropriate for the type of outcome. DISCUSSION: The trial will allow us to determine whether the MCI has an impact on BP and cardiovascular risk factors over a 2-year follow-up period and inform recommendations for health planners in scaling up these strategies for the benefit of society at large. A pre-specified and pre-published statistical analysis plan mitigates reporting bias and data driven approaches. TRIAL REGISTRATION: ClinicalTrials.gov NCT02972619 . Registered on 23 November 2016.