Analysis of Recent Papers in Hypertension

Blood pressure (BP) is not constant throughout the day. Ambulatory BP monitoring (ABPM) done outside of the normal office setting, in which BP measurements are taken at regular intervals (usually every 15 minutes while awake and 30 minutes while asleep) for at least 24 hours, has established the normal circadian pattern of BP. BP characteristically begins to increase between 3 AM and 6 AM and then rapidly increases (surges) on awakening. Over the next few hours after awakening, BP decreases gradually and then remains relatively constant throughout the remaining daytime hours. At night, BP normally ‘‘dips’’ 10% to 20% between midnight and 3 AM when the cycle repeats itself. It has long been known that clinical cardiovascular (CV) events including myocardial infarction (MI), stroke, and sudden cardiac death correlate with the morning BP surge. More recently, however, ABPM studies have informed us that the failure to demonstrate the normal dipping at night is also associated with an increase in CV events. In fact, a recent multivariate analysis has found that it is the nocturnal BP and not the early morning surge that is the key predictor of CV outcomes. The tight relationship between nocturnal BP and CV events has led to the hypothesis that targeting antihypertensive therapy to particular times of day, known as ‘‘chronotherapy’’ may have clinical benefit. However, no previous well-designed prospective study has tested this hypothesis. As nocturnal hypertension frequently occurs in hypertensive individuals with diabetes and those with chronic kidney disease (CKD), evaluating the benefits of timed hypertension treatment on these two populations seems extremely important and an intriguing way to test the validity of the chronotherapy hypothesis. Accordingly, two prospective investigations from one large cohort of Spanish hypertensive patients with diabetes and CKD recently examined whether bedtime administration of at least one antihypertensive medication exerts better BP control and improves CV disease outcomes more than when all medications are taken early in the morning. COMMENTS Current clinical practice finds that most patients take their antihypertensive medications in the morning, often when first arising. While both the Heart Outcomes Prevention Evaluation (HOPE) and Systolic Hypertension in Europe (SystEur) studies administered antihypertensive medication in the evening, no well-designed clinical hypertension outcome trial has specifically studied the concept of chronotherapy, randomizing patients to take their antihypertensive medications at different times of the day to prove whether this improves BP control and CV outcomes. The present two publications, both from subset analysis of the Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular (MAPEC) trial database, found that shifting the timing of at least 1 of 3 antihypertensive medication(s) from morning to evening was more effective in controlling BP (both sleep and 24-hour ABPM) and associated with fewer CV events in patients with hypertension and diabetes or CKD. While this finding is certainly intriguing and the magnitude of the benefit significant, since this is the first and only completed prospective study to favorably assess the role of ABPM and chronotherapy in patients with hypertension, caution must be exercised before we change clinical practice. Strengths of the MAPEC study include the large sample size, the considerable length of follow-up (more than 5 years), and the use of hard clinical endpoints. However, before we change our clinical practice on the basis of this single-center study from Spain, the results need to be replicated in a larger multicenter study evaluating a more diverse ethnic population such as we are likely to encounter in the United States. In addition, the use of baseline 48hour ABPM that was repeated after any medication change or at least yearly throughout the study adds complexity and expense to the clinical design and is not consistent with usual clinical practice, even among most hypertension specialists, in the United States.