First line drug treatment for hypertension and reductions in blood pressure according to age and ethnicity: cohort study in UK primary care

Abstract Objective To study whether treatment recommendations based on age and ethnicity according to United Kingdom (UK) clinical guidelines for hypertension translate to blood pressure reductions in current routine clinical care. Design Observational cohort study. Setting UK primary care, from 1 January 2007 to 31 December 2017. Participants New users of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), calcium channel blockers (CCB), and thiazides. Main outcome measures Change in systolic blood pressure in new users of ACEI/ARB versus CCB, stratified by age (< v ≥55) and ethnicity (black v non-black), from baseline to 12, 26, and 52 week follow-up. Secondary analyses included comparisons of new users of CCB with those of thiazides. A negative outcome (herpes zoster) was used to detect residual confounding and a series of positive outcomes (expected drug effects) was used to determine whether the study design could identify expected associations. Results During one year of follow-up, 87 440 new users of ACEI/ARB, 67 274 new users of CCB, and 22 040 new users of thiazides were included (median 4 (interquartile range 2-6) blood pressure measurements per user). For non-black people who did not have diabetes and who were younger than 55, CCB use was associated with a larger reduction in systolic blood pressure of 1.69 mm Hg (99% confidence interval −2.52 to −0.86) relative to ACEI/ARB use at 12 weeks, and a reduction of 0.40 mm Hg (−0.98 to 0.18) in those aged 55 and older. In subgroup analyses using six finer age categories of non-black people who did not have diabetes, CCB use versus ACEI/ARB use was associated with a larger reduction in systolic blood pressure only in people aged 75 and older. Among people who did not have diabetes, systolic blood pressure decreased more with CCB use than with ACEI/ARB use in black people (reduction difference 2.15 mm Hg (−6.17 to 1.87)); the corresponding reduction difference was 0.98 mm Hg (−1.49 to −0.47) in non-black people. Conclusions Similar reductions in blood pressure were found to be associated with new use of CCB as with new use of ACEI/ARB in non-black people who did not have diabetes, both in those who were aged younger than 55 and those aged 55 and older. For black people without diabetes, CCB new use was associated with numerically greater reductions in blood pressure than ACEI/ARB compared with non-black people without diabetes, but the confidence intervals were overlapping for the two groups. These results suggest that the current UK algorithmic approach to first line antihypertensive treatment might not lead to greater reductions in blood pressure. Specific indications could be considered in treatment recommendations.

Appendix 1: Description of cohort meeting entry criteria, cohort with follow-up BP data and cohort without follow-up BP data Appendix 2: Flowcharts, descriptive characteristics and propensity score distributions before and after matching, CCB vs ACE-I/ARB Appendix 2 Figure 1: Flowchart describing construction of each stratum for CCB versus ACEI/ARB comparisons    Appendix 3: Descriptive characteristics and propensity score distributions before and after matching, thiazides vs CCB Appendix 3 Figure 1: Flowchart describing construction for each stratum for thiazide versus CCB comparison     (-7.29, 5.07) 0.88 (-5.00, 6.77) 2.75 (-6.01, 11.51) *In a non-black, non-diabetic population ** In a non-diabetic population All analyses are 1:1 PS matched within each stratum. Each n consists of half CCB and half ACEI/ARB (or half thiazide and half CCB). For the CCB vs ACEI/ARB comparison a negative result means CCB produced larger reductions in systolic BP and a positive results indicates that ACE-I/ARB produced larger reductions in systolic BP. For the thiazide vs CCB comparison a negative result means thiazides produced larger reductions in systolic BP and a positive results indicates that CCB produced larger reductions in systolic BP. There was a median of 4 (IQR 2-6) BP measurements available during one year follow up for each patient.

Introduction
Background rationale 2 Explain the scientific background and rationale for the investigation being reported. --5 Objectives 3 State specific objectives, including any prespecified hypotheses. --5

Study design 4
Present key elements of study design early in the paper.
-4.a: Include details of the specific study design (and its features) and report the use of multiple designs if used. 4.b: The use of a diagram(s) is recommended to illustrate key aspects of the study design(s), including 6 exposure, washout, lag and observation periods, and covariate definitions as relevant. Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection. --6 Participants 6 (a) Cohort study-give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up. Case-control study-give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls. Cross sectional study-give the eligibility criteria, and the sources and methods of selection of participants.
(b) Cohort study-for matched studies, give matching criteria and number of exposed and unexposed. Case-control study-for matched studies, give matching criteria and the number of controls per case. --See Table 2 Other analyses 17 Report other analyses done-eg, analyses of subgroups and interactions, and sensitivity analyses. --12

Discussion
Key results 18 Summarise key results with reference to study objectives. --13 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias.
19.1: Discuss the implications of using data that were not created or collected to answer the specific research question(s). Include discussion of misclassification bias, unmeasured confounding, missing data, and changing eligibility over time, as they pertain to the study being reported.
19.1.a: Describe the degree to which the chosen database(s) adequately captures the drug exposure(s) of interest.

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Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence.
-20.a: Discuss the potential for confounding by indication, contraindication or disease severity or selection bias (healthy adherer/sick stopper) as alternative explanations for the study findings when relevant.

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Generalisability 21 Discuss the generalisability (external validity) of the study results.

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Other information Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based. --16 Accessibility of protocol, raw data, and programming code 22 -22.1: Authors should provide information on how to access any supplemental information such as the study protocol, raw data, or programming code. -9