The Evaluation of blood pressure treatment stratified according to Central Aortic Systolic Pressure (CASP) in Young Hypertensive Patients - The TREAT CASP study

High blood pressure (BP) is a leading cause of heart disease and strokes and the commonest chronic condition treated in primary care. In the UK, ~25% of all adults and 50% aged over 65yrs have high BP. NICE guidance recommends treatment when BP exceeds 160/100mmHg (called stage II hypertension). NICE also recommends treatment of lower pressures (140-159/90-99mmHg, i.e. stage I hypertension) in those with evidence of damage due to BP, those with diabetes and/or cardiovascular disease (CVD) or those calculated to be at higher risk. However, there is uncertainty what to do about treatment of younger people (aged 40yrs and under) with stage I hypertension because; i) younger people have rarely been included in clinical trials, ii) are unlikely to have developed CVD and iii) risk calculators do not apply to this younger age group. NICE has identified this group of over 1 million younger people as a key priority for research to better identify who would benefit from treatment. BP is routinely measured with a cuff wrapped around the arm and the assumption is made that pressure measured in the arm accurately reflects the pressure in the artery (aorta) close to the heart and the vital organs. We have developed a simple, non-invasive method to measure pressure in the aorta, next to the heart. This pressure is termed "central aortic systolic pressure" or CASP. Importantly, we have shown that pressure in the arm may not be an accurate measure of CASP, especially in younger people. Moreover, CASP is a better predictor of stress on the heart and may better predict stroke and CVD compared to BP measured in the arm. Our study will take place at the UCL vascular physiology unit and will recruit young men (aged 18-40 years) with stage I hypertension. We hypothesise that men with a low CASP (despite a high BP in the arm) actually have a normal BP, with no evidence of strain on the heart and do not need treatment. In contrast, those with a high CASP value will have early evidence of strain on the heart and arteries and will benefit from treatment. We will use MRI to sensitively measure the structure of the heart and the arteries. We will compare in men with high CASP, the effects of treatment for 1 year to lower BP versus no treatment, to see whether lowering CASP improves early heart and artery damage. Our study has no ethical issues as people recruited into the study would not normally receive treatment. We are well placed to conduct this study because of our experience in developing novel ways of measuring CASP, our experience in large clinical trials and in sensitive MRI measurements. The cost of our study is curtailed because of access to our research technology, including our research MRI scanner. Resources requested are to fund staff, clinical tests and consumables. Findings from our study may provide compelling evidence for a better way to stratify younger people with early hypertension who would benefit most from treatment and also avoid long-term treatment of those who would get no benefit.

Research design: This two-stage study incorporates a stage 1 screening study (n=500) to identify men with HIGH and LOW CASP values who will enter a Stage 2 randomized clinical trial (RCT) using a PROBE design (n=130), or an observational follow up study (n=65). Study population: Men aged 18-40 years with stage 1 hypertension (brachial blood pressure 140-159/90-99mmHg) not currently treated and without cardiovascular disease (CVD) or target organ damage. Exclusions include men with secondary hypertension, target organ damage, diabetes, significant arrhythmia. Planned Interventions: Stage 1 has no intervention. The Stage 2 RCT will compare no treatment (control intervention) versus BP lowering (active treatment) according to NICE treatment guidelines for people aged <55years, with titration to achieve a CASP value of <120mmHg and/or at least a 5mmHg reduction from baseline Proposed Outcome Measures:Primary outcome is the change in left ventricular mass index (LVMI) from baseline to study end (12 months), between treatments. Secondary outcomes are markers of cardiovascular damage measured by MRI including LV mass/volume ratio; CMR myocardial tissue tagging; interstitial fibrosis; aortic distensibility; carotid and aortic wall thickness. Albumin excretion rate and retinal photography comprise other outcomes. Assessment & Follow up: In Stage 1, brachial BP and CASP will be measured by CASPro (n=500) which combines a BP monitor with radial tonometry. At the end of Stage 1, 130 men with HIGH CASP and 65 men with LOW CASP values will undergo measurement of LVMI by MRI. In the RCT and observational follow-up (Stage 2), brachial BP and CASP will be monitored at scheduled, 3 monthly follow-up visits, with more frequent visits during titration for the active treatment group. LVMI and secondary outcomes will be measured by MRI after 12 months follow up for all Stage 2 groups. Proposed sample size: The Stage 2 RCT will compare treatment vs. no treatment in groups of 65 men from the HIGH CASP group. We anticipate a change in LVMI between treatments of 6.6 g/m2 based on published data from 4 treatment studies comprising 7 active treatment arms in 627 individuals, SD 10.9g/m2. Power calculations indicate a sample size of 58 people per treatment are required to show a difference in LVMI with 90% power at p=0.05. Statistical analysis: The primary analysis at the end of the Stage 2 will use a linear regression model to compare the change in LV mass from baseline to study end between treatments. A students” t-test will also be used at the end of Stage 1 to compare values for LV mass index between the HIGH and LOW CASP groups. Projected timetables: 500 men with stage 1 hypertension will be identified and screened in the first 18 months of the study (Stage 1). The expected recruitment rate is similar to that of our previous screening studies. A 1 year RCT and an observational follow-up study (Stage 2) will follow completion of Stage 1.