A randomized controlled cross-over trial evaluating differential responses to antihypertensive drugs (used as mono- or dual-therapy) on the basis of ethnicity: The - comparIsoN oF optimal hypertension RegiMens; part of the ancestry informative markers in HYpertension programme – AIM-HY INFORM trial

Research output: Contribution to journalArticlepeer-review

Authors

Colleges, School and Institutes

External organisations

  • University of Cambridge

Abstract

Background
Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of anti-hypertensive therapies. Current UK guidelines employ a ‘black vs white’ approach; in doing so, they ignore the UK's largest ethnic minority, Asians from South Asia.

Study design
The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual-therapy on the basis of self-defined ethnicity. A multi-center, prospective, open-label, randomized study with two parallel, independent trial arms (mono- and dual-therapy), AIM-HY INFORM plans to enroll a total of 1320 patients from across the UK. Those receiving mono-therapy (n = 660) will enter a three-treatment (Amlodipine 10 mg od; Lisinopril 20 mg od; Chlorthalidone 25 mg od), three-period crossover, lasting 24 weeks, whilst those receiving dual-therapy (n = 660) will enter a four-treatment (Amlodipine 5 mg od and Lisinopril 20 mg od; Amlodipine 5 mg od and Chlorthalidone 25 mg od; Lisinopril 20 mg od and Chlorthalidone 25 mg od; Amiloride 10 mg od and Chlorthalidone 25 mg od), four-period crossover, lasting 32 weeks. Equal numbers of three ethnic groups (White, Black/Black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (i.e., 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured eight weeks after each treatment period begins will serve as the primary outcome measure.

Conclusion
AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first and second-line anti-hypertensive therapies for multi-ethnic populations.

Hypertension is the single biggest contributor to the global burden of disease, a burden that is particularly great in lower and middle-income countries (LMIC).1 In high income economies, ethnic minorities - often originating from LMICs - also appear to be disproportionately affected, when compared to indigenous populations.2., 3., 4. Complex interactions between genes and the environment are thought to influence the pathophysiology of essential hypertension, the frequency of hypertension-related complications, and the response to treatment.1 However, data relating to ethnicity are complicated by the plethora of methods used to define ‘ethnicity’ or ‘race’, and a greater understanding of environmental influences has led to the recognition that data collected in one country, may not be readily applicable to similar ethnic groups in distinct geographical locations.1

European guidelines relating to the management of arterial hypertension make no allowance for ethnicity.5 In contrast, the North American guideline, published by the Joint National Committee in 2014, does, stating, “In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB [calcium channel blocker]”.6 Stratified by age and self-defined ethnicity (SDE), the UK's National Institute for Health and Care Excellence (NICE) recommends a third approach, with distinct initial mono-therapies recommended for all those aged 55 years and over, as well as for younger black adults when compared to whites.7 However, the guideline makes no reference to South Asians (i.e. those originating from the Indian sub-continent) - despite the fact that they represent the largest ethnic minority group in the UK at 4.7 million people (52.5 million ‘white British’ citizens being the largest group within a total population of 65.6 million people).7., 8. Furthermore, the afore-mentioned guidelines fail to extend stratification to combination therapy.5., 6., 7.

Stratification on the basis of self-defined ethnicity is potentially flawed by virtue of an increasingly ‘ad-mixed’ population, the complex relationship between ethnicity and phenotype and its inherent cohort based approach which fails to account for inter-individual variations.9 An alternative method of stratification seeks to utilize ancestry informative markers (AIMs) - genetic polymorphisms occurring with substantially different frequencies across populations from distinct geographical regions. Able to predict geographical ancestry, AIMs may capture the genetic component responsible for variations in drug response amongst ethnically diverse populations more discerningly than SDE.9., 10. Concurrent metabolomic profiling of plasma and urine (measurement of low- and intermediate-molecular weight metabolites which reflect the complex inter-play between genetic, physiological, pathophysiological, and/or environmental factors) offers the potential to augment AIMs, with differences between individuals reflecting the entire spectrum of influences, especially diet.11., 12.

In an effort to address these issues, the AIM-HY INFORM trial intends to compare variations in response to antihypertensive agents amongst three cohorts of the UK population stratified on the basis of SDE, whilst also relating any variations to AIMs and metabolomic profiles. In doing so, we hope to evaluate the validity of current NICE guidance which has SDE at the center of its approach to pharmacotherapy, and to examine whether use of AIMs and/or metabolomic profiling results in the more effective personalization of antihypertensive treatment. Furthermore, the trial will evaluate the efficacy of both mono-therapy and dual-therapy across all three cohorts and try to elucidate potential mechanisms underlying any difference in outcomes achieved by using SDE and AIMs. Thus AIM-HY INFORM will enable clinicians to optimize their choice of anti-hypertensive treatments from current, generic, first- and second-line agents, reducing the attrition of antihypertensive therapies.

Hypotheses.

We hypothesize that the response to antihypertensive drugs (used either as mono- or dual-therapy) differs by ethnicity.

Our secondary hypothesis relates to the possibility that ancestry informative markers and metabolites, and/or baseline haemodynamic measurements, are able to predict response to antihypertensive therapy.

Methods
Study design and objectives.

AIM-HY INFORM is a multi-center, prospective, open-label study with two parallel, independent trial arms (mono- and dual-therapy). Eleven UK sites will enroll a total of 1320 patients. Those receiving mono-therapy (n = 660) will enter a three-treatment, three-period crossover, lasting 24 weeks, whilst those receiving dual-therapy (n = 660) will enter a four-treatment, four-period crossover, lasting 32 weeks. Equal numbers of all three ethnic groups (White, Black/Black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (i.e., 220 participants per ethnic group per arm).

The primary objective of the AIM-HY INFORM trial is to determine whether the response to antihypertensive drugs differs on the basis of SDE. Secondary objectives (Table 1) include an evaluation of this response on the basis of AIMs, baseline metabolomics, baseline haemodynamic data, genomics and a more detailed evaluation of SDE (with a family tree extending to three generations, i.e., grandparents). Additionally, the trial aims to determine: 1) the most effective mono- and dual-therapy for hypertension, and any variation(s) by ethnicity, 2) whether metabolomics and haemodynamics differ by ethnicity, and 3) whether previously identified biomarkers (i.e., those derived from other cohorts e.g. the USA) can predict the therapeutic response observed. Further exploratory, tertiary objectives, may be defined.

Study population, treatment assignment and randomization.

The inclusion and exclusion criteria are listed in Table 2. Hypertensive adults aged between 18 and 65 years are eligible for inclusion, provided that they are able to self-identify with one of the three ethnicities outlined. Treatment-naïve individuals will be confined to the mono-therapy arm. Those who have previously been treated/are being treated with anti-hypertensive agents will be able to enter either arm, provided they are able to under-go a washout of 2–4 weeks; if not, they will be assigned to dual-therapy. (See Table 1.)

Details

Original languageEnglish
JournalAmerican Heart Journal
Early online date20 May 2018
Publication statusE-pub ahead of print - 20 May 2018