Title: Inter-arm blood Pressure difference, cardiovascular events, cerebrovascular disease and mortality: an Individual Patient Data meta-analysis (INTERPRESS-IPD)
Funder: Department of Health and Social Care

Abstract: Background An inter-arm difference in blood pressure between arms (IAD) is regularly encountered in clinical practice. Differences &ge;10mmHg in systolic pressures are seen in 11% of hypertensive subjects, 7% of people with diabetes and 4% of the general population. Individual cohort studies have prospectively associated systolic IAD with higher cardiovascular and all-cause mortality rates, and increased cardiovascular event rates. Our 2012 meta-analysis (which aggregated only summary data from studies, and could not conduct individual patient level data analyses as now proposed) reported a pooled hazard ratio of 1.7 (1.1 to 2.5) for cardiovascular death with a systolic IAD &ge;15mmHg. Since that review other cohort studies have reported similar findings, however several important questions remain which cannot be answered by study level analyses and require the added power of an individual patient data level meta-analysis. Aims We are forming an international collaboration (the INTERPRESS IPD collaboration ) to combine individual patient data from IAD cohort studies and form a single large dataset suitable for individual patient data meta-analysis. This will allow us to address the following research questions: 1. What is the additional contribution of systolic IAD to prognostic risk estimation for cardiovascular fatal and non-fatal events, and all-cause mortality? 2. What is the cut-off value for systolic IAD that defines elevated risk, and is there a relationship between increasing IAD and increasing risk? 3. Do different methods of IAD measurement have an impact on the prognostic value of IAD measurements? The individual patient data will also be used to describe the epidemiology of IAD with a level of detail that has not previously been possible, for example by analysing variations in the prevalence of IAD across different age, gender, and ethnic groupings, and reporting the risk factors or disease conditions associated with the presence of an IAD. Investigation plan The INTERPRESS individual patient data meta-analysis project will: 1. Undertake updated literature searches for hitherto unknown IAD datasets and obtain individual patient data from study investigators. 2. Combine individual patient data from prospective cohorts that measured blood pressure in both arms during recruitment. 3. Develop a standardised multivariable model of risk for cardiovascular events, and total mortality, to establish the additional contribution of systolic IAD to risk prediction. In doing so we will develop a new prognostic model for cardiovascular risk estimation that includes IAD. 4. Explore variation in the additional risk contribution of IAD across pre-defined subgroups based on underlying health status (e.g. with or without hypertension) and ethnicity. 5. Establish the lower limit of contribution to additional cardiovascular risk prediction for IAD, to define a new clinically important cut-off value for IAD based on prognostic value. 6. Undertake subgroup analysis by method of IAD measurement to explore any effect of measurement protocol on risk prediction by IAD. 7. Undertake cross-sectional analyses to describe the epidemiology of IAD in the dataset. Potential benefits to patients and the NHS UK and international blood pressure guidelines advise checking for an IAD. This advice is often ignored in practice due to lack of clarity, yet systolic IAD is a recognised risk marker that is readily assessed in any patient. A positive outcome from this study will offer: 1. confirmation of the role of IAD as a risk marker 2. definition of the minimum clinically important size of IAD 3. increased precision of cardiovascular risk estimation, to inform patients and inform their lifestyle choices more accurately. Our results will update national and international guidelines regarding the measurement and meaning of IAD, and we will describe the risk factors associated with IAD to empower clinicians to identify patients in whom an IAD should be looked for.

Lay abstract: When blood pressure is measured a significant minority of people have different readings in their left and right arms. Studies which follow up people with such inter-arm differences over a number of years have shown increased rates of death in those with inter-arm differences compared to those without. A number of studies have reported these findings but important questions remain. We seek to combine existing study data from around the world in an individual patient data meta-analysis. We will collate the original information for every participant from each study. By combining data we will create the largest such dataset of adults with blood pressure measured in both arms. This combined dataset will give better overall estimates of the additional risk of events attributable to inter-arm differences, and allow examination of the following questions: 1. What additional contribution does inter-arm blood pressure difference make to existing prediction of future cardiovascular risk? 2. What size of inter-arm difference indicates an elevated risk? In other words what is the minimum clinically important inter-arm difference? 3. Do different methods of measuring inter-arm difference (both arms simultaneously or one after the other) affect the value of the measured inter-arm difference as a risk marker? Individual patient data analysis combines existing data, and ensures that it is all analysed in the same way for substantially lower costs than a new study of equivalent size (over 17,000 participants) would require. It overcomes important limitations to the conclusions that can be drawn from meta-analyses restricted to the published data alone, where analysis methods and reporting differ between individual studies. We believe that, in answering the questions posed, we will inform clinical practice through updated international blood pressure guidelines, and provide patients and clinicians with robust evidence to inform health care decisions when an inter-arm difference is detected.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR