Refractory hypertension focus on nighttime blood pressure and nondipping

In the past decades, a growing number of investigations, performed in different clinical settings, has been devoted to circadian variations in blood pressure (BP) and to nocturnal BP levels with the aim to clarify their associations with demographic/clinical variables, conventional risk factors, subclinical organ damage, and incident cardiovascular disease. In particular, two lines of clinical research have investigated this issue focusing on the nondipping status and nocturnal hypertension.1, 2

Although nondipping status, as opposed to the dipping status, is commonly regarded as a clinical trait characterized by more advanced organ damage and a worse cardiovascular prognosis, this issue is still largely debated. This is because a number of studies have failed to show differences in intermediate end points such as cardiac and extracardiac target organ damage and hard outcomes between nondippers and dippers after adjustment for several confounders including average 24‐hour BP values.3, 4 Moreover, it should be noted that a full preserved BP fall at night (ie, dipping status) may not necessarily result in a normal nighttime BP profile, as defined by the cutoff limits (ie, <120/70 mm Hg) recommended by authoritative hypertension guidelines.5 This means that dipping status and nocturnal normotension may be dissociated and represent different ambulatory BP phenotypes as shown by an increasing body of evidence supporting the view that elevated nocturnal BP values may frequently coexist with a normal day–night BP fall,6 and that nocturnal hypertension, independently of dipping status, is a powerful correlate of target organ damage as well as an independent predictor of cardiovascular events.7, 8

In this issue of the Journal, Irvin and colleagues9 report the results of a comprehensive observational study aimed at answering two relevant questions: (1) Is there a relationship between refractory hypertension (RH) and nighttime hypertension and/or nondipping pattern? and (2) Are nighttime hypertension or nondipping pattern independent predictors of incident RH? To answer these questions they analyzed cross‐sectional and longitudinal data from a subset of participants with treated hypertension enrolled in the Jackson Heart Study, a community‐based cohort of black patients.

The authors found that both nighttime hypertension and nondipping BP were significantly more frequent in patients with RH than in their counterparts with controlled BP. On the contrary, none of these two BP phenotypes were found to be associated with development of RH during a long‐term follow‐up period, after adjustment for major confounders. Before commenting on these findings in detail, some general considerations on available evidence in this research area may be useful.

Uncontrolled hypertension is associated with an increasing incidence of cerebrovascular and cardiovascular events such as stroke, heart failure, myocardial infarction, peripheral artery disease, and chronic kidney disease across all age strata and ethnicities. RH is a subset of uncontrolled BP recognized as a condition associated with an extremely high cardiovascular risk. According to European Society of Hypertension/European Society of Cardiology guidelines,5 hypertension is defined as resistant to treatment or refractory when a therapeutic plan including attention to lifestyle measures and prescription of at least three drugs in adequate doses (including a diuretic) fails to sufficiently lower systolic and diastolic BP (ie, <140/90 mm Hg). Other authoritative guidelines also classify all patients treated with four or more antihypertensive classes regardless of their BP values as resistant.10 Depending on the population examined and the level of medical workup, the prevalence of RH has been described to range from 5% to 25% of the whole hypertensive population, with figures <10%, probably reflecting the true prevalence. Recent data provided by a national survey on a sample of an Italian population with hypertension including 1117 patients, showed that, accounting for only pharmacological treatment criteria, the prevalence of RH was 8.2%.11 Interestingly, also incorporating in RH diagnosis, the adherence to appropriate lifestyle measures, such as dietary salt restriction (Na 24 hours <100  mmol) and normal body mass index, RH prevalence fell to 2.2% and 0.8%, respectively. RH can be real or apparent. A frequent cause of apparent or spurious RH is failure to adhere to the prescribed drug regimen, or perhaps, more frequently, to systematically follow lifestyle changes. Lack of adequate BP control may, however, also depend on an alerting reaction to the BP‐measuring procedure, which occurs exclusively in the medical setting (isolated office RH).

The impact of this alarm reaction on the occurrence of resistant hypertension seems to be highly variable among different studies, ranging from 20% to 43% of patients.12 The BP‐CARE (BP Control Rate and Cardiovascular Risk Profile) study aimed to assess the prevalence and main clinical features of RH in 1312 patients with treated hypertension living in nine central and east European countries showed that pseudo RH (either noncompliant or white‐coat) was present in approximately 13% of the sample.13

The underlying causes/mechanisms of true RH are multiple and include obesity, high sodium intake, excessive alcohol consumption, obstructive sleep apnea (usually but not always associated with obesity), undiagnosed secondary forms of hypertension, older age, ethnicity (black race), and advanced and irreversible target organ damage especially when it compromises renal function and large artery distensibility or leads to marked arteriolar remodeling characterized by an increase in wall‐lumen ratio.14 Similarly, the mechanism(s) of abnormal circadian BP pattern is multifactorial. Indeed, a blunted BP fall at night (and nocturnal hypertension) has been shown to be highly prevalent in a wide array of conditions including secondary hypertension, chronic kidney diseases, types 1 and 2 diabetes mellitus, sleep apnea syndrome, autonomic nervous system dysfunction, and abnormal renal sodium excretion capacity.15 On the whole, these clinical and epidemiological observations underline how RH and alterations in circadian BP rhythm share similar mechanisms and comorbidities.

The cross‐sectional findings provided by Irvin and colleagues,9 conducted in 540 patients with treated hypertension (mean age 62 ± 9 years, 76% female) from a community‐based cohort of blacks with prevalent obesity (57%) and type 2 diabetes mellitus (33%), add a new piece of information in this research area, showing that RH is associated with nondipping status and nocturnal hypertension, independently of several confounders such as age, sex, obesity, obstructive sleep apnea risk, physical activity, current smoking, diabetes mellitus, chronic kidney disease, prior cardiovascular disease, and daytime systolic and diastolic BP.

In patients with RH (n = 43, 8.2%) the risk of having a nondipping profile and nighttime hypertension was 20% and 25% higher than in their counterparts without it, respectively. Prevalence rates of nondipping status were 88% in patients with RH and 66% in controls, and corresponding figures for nocturnal hypertension were 84% and 58%, respectively. Other important aspects concerning this part of the study can be summarized as follows: (1) none of the patients with RH had mean 24‐hour BP values <130/80 mm Hg and, therefore, the absence of spurious RH makes these results even more solid; (2) treatment with four or more antihypertensive drugs was independently associated with higher prevalence of both nocturnal hypertension and nondipping; (3) this was also the case for the treatment with an α₁ antagonist, whereas α₂ agonists and other centrally acting agents were associated with a higher prevalence of nocturnal hypertension only; and (4) on the contrary, diuretic treatment was associated with a lower prevalence of nondipping. As impaired renal capacity to excrete sodium has been shown to be a factor leading to a blunted nocturnal BP fall, it is conceivable that different effects of antihypertensive drugs on plasma volume and sodium balance may have an opposite influence on nocturnal pressure and magnitude of day/night BP variations. At the end of the 1990s, Uzu and colleagues16 evaluated the effect of a short‐term thiazide treatment in patients with hypertension with dipper and nondipper status and found that the extent of nocturnal BP fall was unaffected by treatment in dippers. On the contrary, it was markedly enhanced in nondippers, mostly reverted to normal circadian rhythm.

As for the value of baseline nocturnal hypertension and nondipping in predicting new cases of RH, the longitudinal data of this study, collected over a 7‐year period of follow‐up, did not show an independent relationship between both BP phenotypes and incident RH, accounting for about one quarter of the whole sample. It is worth noting that while nondipping status was not associated with incident RH before or after multivariable adjustment, nocturnal hypertension lost its association only when daytime systolic and diastolic BP was forced in the model.

This finding, obtained in a black population with a high prevalence of nocturnal hypertension and nondipping, cannot be extrapolated to other ethnic groups and further investigations in this field are needed.

Finally, an important limitation of the present study deserves mention. Although recent reports suggest that nondipping (and nocturnal hypertension) is partly related to the absence of homogeneous 24‐hour therapeutic coverage in patients treated with single morning doses, no attention was paid in this analysis to the time of day of antihypertensive treatment.17, 18 Therefore, this article cannot provide information on the impact of treatment time (morning or bedtime administration of antihypertensive drugs) on nocturnal BP and dipping status in patients with RH and in controls.

In conclusion, the study by Irvin and colleagues9 raises some important issues regarding the complex relationship between RH, nocturnal BP phenotypes, and the influence of certain classes of drugs on circadian BP rhythm. These topics need to be further clarified in order to optimize treatment strategies and cardiovascular prevention in patients with uncontrolled hypertension.

DISCLOSURE

The authors report no conflicts of interest.

Cuspidi C, Tadic M, Grassi G. Refractory hypertension focus on nighttime blood pressure and nondipping. J Clin Hypertens. 2018;20:447–449. 10.1111/jch.13196