Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: Rationale and design of the Hygia Project

ABSTRACT

This article describes the rationale, objectives, design and conduct of the ambulatory blood pressure monitoring (ABPM)-based Hygia Project. Given the substantial evidence of the significantly better prognostic value of ABPM compared to clinic BP measurements, several international guidelines now propose ABPM as a requirement to confirm the office diagnosis of hypertension. Nonetheless, all previous ABPM outcome investigations, except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study (MAPEC) study, relied upon only a single, low-reproducible 24 h ABPM assessment per participant done at study inclusion, thus precluding the opportunity to explore the potential reduction in cardiovascular disease (CVD) risk associated with modification of prognostic ABPM-derived parameters by hypertension therapy. The findings of the single-center MAPEC study, based upon periodic systematic 48 h ABPM evaluation of all participants during a median follow-up of 5.6 years, constitute the first proof-of-concept evidence that the progressive reduction of the asleep systolic blood pressure (SBP) mean and correction of the sleep-time relative SBP decline toward the normal dipper BP profile, most efficiently accomplished by a bedtime hypertension treatment strategy, best attenuates the risk of CVD, stroke and development of new-onset diabetes. The Hygia Project, primarily designed to extend the use of ABPM in primary care as a requirement for diagnosis of hypertension, evaluation of response to treatment and individualized assessment of CVD and other risks, is a research network presently composed of 40 clinical sites and 292 investigators. Its main objectives are to (i) investigate whether specific treatment-induced changes in ABPM-derived parameters reduce risk of CVD events, stroke, new-onset diabetes and/or development of chronic kidney disease (CKD); and (ii) test the hypothesis that bedtime chronotherapy entailing the entire daily dose of ≥1 conventional hypertension medications exerts better ambulatory BP control and CVD, metabolic and renal risk reduction than all such medications ingested in the morning upon awakening. Between 2007 and 2015, investigators recruited 18 078 persons [9769 men/8309 women, 59.1 ± 14.3 years of age (mean ± SD)], including 15 764 with hypertension according to ABPM criteria as participants in the prospective randomized chronotherapy trial. The initial evaluation includes 48 h ABPM, detailed medical history and screening laboratory blood and urine tests. The same evaluation procedure is scheduled annually, or more frequently when treatment adjustment is required for proper ambulatory BP control, targeting a median follow-up of >5 years. The primary CVD outcome end point is the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, ischemic stroke and hemorrhagic stroke. The independent Hygia Project Events Committee periodically evaluates blinded clinical reports to ascertain and certify every documented event. Beyond the potential findings resulting from testing the main hypotheses, the Hygia Project has already demonstrated, as proof of concept, that the routine diagnosis of hypertension and individualized assessment of CVD and other risks by ABPM, as currently recommended, is fully viable in the primary care setting, where most people with either hypertension, dyslipidemia, type 2 diabetes or CKD receive routine medical attention.

KEYWORDS:

• ambulatory blood pressure monitoring
• cardiovascular risk
• chronic kidney disease
• circadian rhythm
• diabetes
• hypertension chronotherapy
• sleep-time blood pressure

Acknowledgements

The Hygia Project has been endorsed by the International Society for Chronobiology (ISC) and the Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC). The authors fully appreciate the critical comments, suggestions and recommendations provided at all stages of the study by Michael H. Smolensky and Francesco Portaluppi.

Declaration of interest

The Hygia Project is an independent investigator-promoted study supported by unrestricted grants from Ministerio de Ciencia e Innovación, Spanish Goverment (SAF2009-7028-FEDER); Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government (PI14-00205); Consellería de Economía e Industria, Dirección Xeral de Investigación e Desenvolvemento, Galician Regional Government (INCITE08-E1R-322063ES; INCITE09-E2R-322099ES; 09CSA018322PR; IN845B-2010/114); Consellería de Cultura, Educación e Ordenación Universitaria, Galician Regional Government (CN2012/251; GPC2014/078); European Regional Development Fund (ERDF) and the Galician Regional Government under agreement for funding the Atlantic Research Center for Information and Communication Technologies (AtlantTIC); and Vicerrectorado de Investigación, University of Vigo. This funding body has no role in the study design, analysis and interpretation of data, writing of the reports or the decision to submit articles for publication.