Ambulatory Blood Pressure for Cardiovascular Risk Stratification

Introduction For practical reasons, blood pressure values measured by physicians or nurses in a medical environment remain the clinical basis of the diagnosis and management of arterial hypertension around the world as recommended by all guidelines [1–4]. Nevertheless, measurements of blood pressure outside the office have gained an increasing popularity over the last decades not only to ascertain the diagnosis of hypertension but also to follow the impact of therapeutic interventions. Out-of-office blood pressure measurements can be obtained either by 24-h ambulatory blood pressure monitoring or by home blood pressure monitoring. As reviewed recently [5], both sets of out-of-office blood pressure offer undeniable advantages when compared to office blood pressure. First, both ambulatory blood pressure and home blood pressure monitoring provide more reliable and reproducible information on blood pressure. Second, blood pressure values obtained by ambulatory blood pressure and home blood pressure monitoring appear to be more closely related to target organ damage than office blood pressure and hence have a greater prognostic relevance than office blood pressure. Third, certain diagnosis such as white coat hypertension and masked hypertension can only be diagnosed using out-of-office blood pressure measurements. Fourth, when used in the clinical follow-up of treated hypertensive patients to evaluate the impact of drug treatment, ambulatory blood pressure monitoring as well as home blood pressure monitoring has the advantage of not being affected by a placebo effect. Finally, evidence has been provided that treatment-induced reduction in 24-h blood pressure may predict better than office blood pressure the regression of end organ damage (particularly the cardiac one) induced by antihypertensive drug. Many of these information have been achieved during the past two decades by a number of studies carried out in different populations around the world, including the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study [6–10]. When should out-office blood pressure be measured? Despite their advantages, ambulatory blood pressure monitoring as well as home blood pressure monitoring is not regarded as a routine procedure that should be applied to all hypertensive patients essentially for economical reasons. However, this issue is debated because the clinical information gathered with these measurements may potentially result in financial savings when applied adequately. The European and American guidelines for the management of hypertension have defined some indications for the use of ambulatory blood pressure monitoring in hypertension [1,2]. These include patients with resistant hypertension, patients with a high variability of office blood pressure, low-risk patients with a high blood pressure, patients with suspected episodes of hypotension, patients with a large discrepancy between office and home blood pressures, and finally patients with special clinical conditions such as pregnancy or sleep apnea syndrome. Outside these indications, the use of ambulatory blood pressure monitoring could be discussed both in terms of feasibility and economics. Theoretically, a measurement of out-of-office blood pressure could be recommended to all new patients with as suspected hypertension to confirm the diagnosis of hypertension and to refine the patient's cardiovascular risk profile. Therefore, ambulatory blood pressure monitoring could be recommended to all high cardiovascular risk patients before starting any treatment and later under therapy to ascertain the adequacy of the control of blood pressure. Ambulatory blood pressure values in diabetic patients In this issue of the Journal of Hypertension, Leitao et al.[11] report the results of a cross-sectional study performed to estimate the daytime ambulatory blood pressure monitoring values corresponding to the target office blood pressure of 130/80 mmHg for diabetic (as defined by the American Diabetes Association) and to assess which diabetic patients may actually benefit from ambulatory blood pressure monitoring. They included 554 patients in this analysis. Regression analyses were performed to analyze the ambulatory blood pressure monitoring values corresponding to office blood pressure and receiver operating characteristics (ROC) curves were used to assess the sensitivity and specificity of office blood pressure in diagnosing daytime ambulatory blood pressure monitoring hypertension. According to their regression equations, the daytime ambulatory blood pressure monitoring corresponding to the target office blood pressure of 130/80 mmHg was 129/79 mmHg and the daytime ambulatory blood pressure monitoring value corresponding to 140/90 mmHg at the office was 134/82 mmHg. As expected, discrepancies between ambulatory blood pressure monitoring and office blood pressure were due essentially to masked hypertension (about 10% of cases) and white coat hypertension (between 19% for systolic blood pressure and 26% for diastolic blood pressure). Interestingly, when office blood pressure was lower than 120 mmHg systolic and 70 mmHg diastolic, the sensitivity to rule out hypertension using ambulatory blood pressure monitoring was 90%. Similarly, when office blood pressure was more than 145 mmHg systolic and more than 90 mmHg diastolic the sensitivity to confirm hypertension using ambulatory blood pressure monitoring was 90%. Within these two sets of limits, 38% of patients would be misclassified if only office blood pressure values would be considered for the diagnosis. Thus, using the cut-off values of less than 120/70 mmHg and more than 140/90 mmHg at the office, 56% of the population sample would need an ambulatory blood pressure monitoring to confirm the diagnosis of hypertension. According to these results, only diabetics with an office blood pressure between 120 and 140 mmHg systolic and/or a diastolic blood pressure between 70 and 90 mmHg would really benefit from an out-office assessment of blood pressure. This would limit the use of ambulatory blood pressure monitoring to only 50% of the diabetic patients. Studies implications and limitations The results of this provide interesting practical information on the use of ambulatory blood pressure monitoring in diabetic patients. However, they also have some limitations. The first one is the fact that the entire analysis is based on daytime ambulatory blood pressure only. Although the authors have measured 24-h blood pressure, they have not considered the nighttime blood pressure. This is unfortunate because there is increasing evidence that nighttime is a better predictor of cardiovascular risk than daytime blood pressure. Moreover, diabetic patients are often characterized by an absence of the physiological fall in blood pressure reflecting a nondipping pattern at night. Diabetes may even be the cause of a reverse dipping, that is an increase in blood pressure at night. Both the nondipping and the reverse dipping pattern of blood pressure have been associated with an increased risk of developing target organ damages such as left ventricular hypertrophy, microalbuminuria, renal dysfunction, and cerebral vascular lesions [5,12]. Thus, when assessing the cardiovascular risk profile linked to hypertension in diabetic patients, nighttime blood pressure should be included. Indeed, it is not uncommon in diabetes that daytime normotensive patients exhibit a nocturnal hypertension. This type of patients would be misdiagnosed using the algorithm proposed by the authors. Recently, the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial have shown that in diabetic patients the reduction of cardiovascular morbidity and mortality obtained by lowering office blood pressure below 120 mmHg systolic is not greater than that seen reducing blood pressure below 130 mmHg [13]. On the contrary, a systolic blood pressure below 120 mmHg may result in an increased risk of developing cardiac complications, as suggested by the recent post hoc analysis of diabetic patients with coronary heart diseases having participated in the INternational VErapamil SR-Trandolapril (INVEST) Study [14]. If a low blood pressure increases the risk of cardiac complications in diabetics, one might have to reconsider the necessity to perform an ambulatory blood pressure monitoring in diabetic patients with a blood pressure <120/70 mmHg in contrast to the proposals of Leitao et al. Indeed, in treated diabetic patients with a low office blood pressure, ambulatory blood pressure monitoring could be of importance to diagnosis episodes of asymptomatic hypotension episodes which might increase their cardiac risk. Thus, in the analysis of daytime and nighttime blood pressure values, it would be of interest to assess whether the percentage of ambulatory blood pressure values below a certain level is indeed associated with an increased risk of some cardiovascular complications. In this respect, it is important to mention that the analysis presented by Leitao et al. does not provide any information on the presence in this particular patients population of cardiac organ damage. The study also does not provide any data such on the occurrence of cardiovascular events and deaths, as it was not a prospective cohort study. Both these two sets of information should be thus provided by future clinical trials.

How common is isolated nocturnal hypertension?

Guidelines recommend measuring out-of-clinic blood pressure (BP) to identify masked hypertension (MHT) defined by out-of-clinic BP in the hypertensive range among individuals with clinic-measured BP not in the hypertensive range. The aim of this study was to determine the overlap between ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM) for the detection of MHT. We analyzed data from 333 community-dwelling adults not taking antihypertensive medication with clinic BP <140/90 mm Hg in the IDH study (Improving the Detection of Hypertension). Any MHT was defined by the presence of daytime MHT (mean daytime BP ≥135/85 mm Hg), 24-hour MHT (mean 24-hour BP ≥130/80 mm Hg), or nighttime MHT (mean nighttime BP ≥120/70 mm Hg). Home MHT was defined as mean BP ≥135/85 mm Hg on HBPM. The prevalence of MHT was 25.8% for any MHT and 11.1% for home MHT. Among participants with MHT on either ABPM or HBPM, 29.5% had MHT on both ABPM and HBPM; 61.1% had MHT only on ABPM; and 9.4% of participants had MHT only on HBPM. After multivariable adjustment and compared with participants without MHT on ABPM and HBPM, those with MHT on both ABPM and HBPM and only on ABPM had a higher left ventricular mass index (mean difference [SE], 12.7 [2.9] g/m2, P<0.001; and 4.9 [2.1] g/m2, P=0.022, respectively), whereas participants with MHT only on HBPM did not have an increased left ventricular mass index (mean difference [SE], -1.9 [4.8] g/m2, P=0.693). These data suggest that conducting ABPM will detect many individuals with MHT who have an increased cardiovascular disease risk.

This issue of Hypertension includes an article by Bur et al1 that focuses on the comparison between clinic and ambulatory blood pressure (ABP) values in patients with moderate to severe hypertension. The primary goal of the Bur study was to obtain a classification of hypertensive patients, based on the ABP values corresponding to the clinic blood pressure (BP) values that have been used to stage hypertension by the World Health Organization–International Society of Hypertension (WHO-ISH) and the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) VI guidelines.2,3 An additional goal was to evaluate whether this ABP-based classification has prognostic value, as shown for the prognostic value of the clinic BP staging. Both clinic BP and ABP were measured in 736 hypertensive patients (557 of whom were under treatment) at the time of their first admission to the local Hypertension Unit. All patients then entered a follow-up period with an average duration of 52 months (range, 6 to 96 months), during which only clinic BP was obtained. During the observation time, 82 patients had nonfatal cardiovascular events and 9 patients died of cardiovascular causes. The article adds interesting information to the existing database on the clinical value of ABP. In particular, it contributes to the available knowledge on the prognostic importance of ABP as well as on its relation to clinic BP in the context of treating patients in a hypertension center.4 Stratifying patients into different risk categories on the basis of ABP values requires studies that (1) establish in populations or in large groups of hypertensive patients the relation of cardiovascular morbidity and mortality with the different 24-hour ABP values selected5,6 and (2) evaluate how prognosis of patients is modified when ABP is reduced by treatment, leading to a change in …

An algorithm for making a differential diagnosis between sustained and white coat hypertension (WCH) has been proposed - patients with office hypertension undergo home blood pressure monitoring (HBPM) and those with normal HBP levels undergo ambulatory blood pressure monitoring (ABPM). We tested whether incorporating an upper office blood pressure (OBP) cut-off in the algorithm, higher than the traditional 140/90 mmHg, reduces the need for HBPM and ABPM. Two hundred twenty-nine normotensive and untreated mildly hypertensive participants (mean age 52.5 +/- 14.6 years, 54% female participants) underwent OBP measurements, HBPM, and 24-h ABPM. Using the algorithm, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) for sustained hypertension and WCH were assessed. We then modified the algorithm utilizing a systolic and diastolic OBP cut-off at a specificity of 95% for ambulatory hypertension - those with office hypertension but OBP levels below the upper cut-off underwent HBPM and subsequent ABPM, if appropriate. Using the original algorithm, sensitivity and PPV for sustained hypertension were 100% and 93.8%, respectively. Despite a specificity of 44.4%, NPV was 100%. These values correspond to specificity, NPV, sensitivity, and PPV for WCH, respectively. Using the modified algorithm, the diagnostic accuracy for sustained hypertension and WCH did not change. However, far fewer participants needed HBPM (29 vs. 84) and ABPM (8 vs. 15). In this sample, the original and modified algorithms are excellent at diagnosing sustained hypertension and WCH. However, the latter requires far fewer participants to undergo HBPM and ABPM. These findings have important implications for the cost-effective diagnosis of sustained hypertension and WCH.

Masked hypertension, defined as nonelevated clinic blood pressure (BP) and elevated out-of-clinic BP may be an intermediary stage in the progression from normotension to hypertension. We examined the associations of out-of-clinic BP and masked hypertension using ambulatory BP monitoring with incident clinic hypertension in the Jackson Heart Study, a prospective cohort of blacks. Analyses included 317 participants with clinic BP <140/90 mm Hg, complete ambulatory BP monitoring, who were not taking antihypertensive medication at baseline in 2000 to 2004. Masked daytime hypertension was defined as mean daytime blood pressure ≥135/85 mm Hg, masked night-time hypertension as mean night-time BP ≥120/70 mm Hg, and masked 24-hour hypertension as mean 24-hour BP ≥130/80 mm Hg. Incident clinic hypertension, assessed at study visits in 2005 to 2008 and 2009 to 2012, was defined as the first visit with clinic systolic/diastolic BP ≥140/90 mm Hg or antihypertensive medication use. During a median follow-up of 8.1 years, there were 187 (59.0%) incident cases of clinic hypertension. Clinic hypertension developed in 79.2% and 42.2% of participants with and without any masked hypertension, 85.7% and 50.4% with and without masked daytime hypertension, 79.9% and 43.7% with and without masked night-time hypertension, and 85.7% and 48.2% with and without masked 24-hour hypertension, respectively. Multivariable-adjusted hazard ratios (95% confidence interval) of incident clinic hypertension for any masked hypertension and masked daytime, night-time, and 24-hour hypertension were 2.13 (1.51-3.02), 1.79 (1.24-2.60), 2.22 (1.58-3.12), and 1.91 (1.32-2.75), respectively. These findings suggest that ambulatory BP monitoring can identify blacks at increased risk for developing clinic hypertension.

Although fixed-dose combination drug therapy is commonly used to treat hypertension, the efficacy of head-to-head comparisons of dual fixed-dose combinations has not been well described. We hypothesized that when used in combination with an angiotensin receptor blocker (ARB) olmesartan medoxomil, hydrochlorothiazide (HCTZ) will be as effective as the dihydropyridine calcium channel blocker (CCB) amlodipine to lower both clinic and 24-h ambulatory blood pressure (BP). Furthermore, we hypothesized that response to ARB along with HCTZ or ARB along with CCB may be heterogeneous depending on clinical characteristics. An individual-level meta-analysis was performed among 559 individuals treated with dual combination therapy in five trials. A forced titration scheme was used in each of these trials and blood BP was measured both in the clinic and outside using 24-h ambulatory BP monitors. The mean age was 62 years, 55% were men, 46% had diabetes mellitus, 17% were black, clinic BP averaged 159.5/89.5 mmHg and 24-h ambulatory BP 145.0/82.5 mmHg. Overall, baseline-adjusted lowering of mean 24-h ambulatory BP was 22.0/11.7 mmHg. BP reductions were similar between ARB along with HCTZ and ARB along with CCB groups. However, clinic BP was lowered 4.3/1.8 mmHg more with ARB along with CCB combination (28.4/13.0 mmHg drop) than with ARB along with HCTZ combination (24.1/11.2 mmHg drop). The white coat effect (WCE) was therefore mitigated 3.8/1.7 mmHg more with ARB along with CCB combination. Heterogeneity in ambulatory BP response was noted. Compared with men, women had a greater ambulatory and clinic BP lowering with either combination. ARB along with HCTZ produced a greater BP-lowering effect among men, elderly, nonobese and nondiabetic. On the contrary, ARB along with CCB produced a greater BP-lowering effect among women, young, obese and diabetic individuals. This heterogeneity in response was often undetectable with clinic BP measurements. In multivariable analysis, sex and diabetes mellitus remained independent measures of heterogeneity. Overall, the combination of olmesartan and HCTZ is as effective as olmesartan and CCB in lowering 24-h, daytime, and night-time ambulatory BP. However, greater lowering is noted with the olmesartan and CCB combination for clinic BP. Thus, out-of-office BP monitoring is necessary to provide better assessment of overall BP and response to treatment. Women and diabetic individuals may have slightly better 24-h ambulatory BP response with the olmesartan and CCB combination therapy.

Purpose: Population-based studies estimating prevalence’s of white-coat, masked and sustained hypertension in non-European adolescents are needed, particularly in developing countries. Aiming to determine these estimates and, additionally identify factors associated to these conditions this study was conducted.Materials and methods: Cross-sectional study with a representative sample of secondary school students from a Brazilian state capital. Office measurements were performed with validated semi-automatic devices. Home BP (blood pressure) monitoring protocol included two day-time and two evening-time measurements over 6 days. Adolescents’ were classified as: normotensives (office and home BP <95th percentile); sustained hypertensives (office and home BP ≥95th percentile); white-coat hypertensives (office BP ≥95th percentile and home BP <95th percentile) and masked hypertensives (office BP <95th percentile and home BP ≥95th percentile). Logistic regression models were built to identify if sex, age, BMI and family history of HTN were independently associated with white-coat, masked and sustained hypertension.Results: In a sample of 1024 adolescents, prevalence of white-coat, masked and sustained hypertension was 7.5%, 2.2% and 1.7%, respectively. Male sex was positively associated with white-coat hypertension (OR 2.68; 95%CI 1.58–4.54; p < 0.001). BMI was positively associated with both white-coat (OR 1.23; 95%CI 1.16–1.30; p < 0.001) and sustained hypertension (OR 1.19; 95%CI 1.11–1.29; p < 0.001). None of the independent variables were associated with masked hypertension in this population.Conclusion: The estimated prevalence of white-coat hypertension, masked and sustained hypertension in a population of non-European adolescents assessed by home BP monitoring was 7.5%, 2.2% and 1.7% respectively. Male sex was positively associated with white-coat hypertension in these adolescents while BMI was positively associated with both white-coat and sustained hypertension.

Aim: To compare the accuracy of clinic blood pressure (CBP) and telemedical home blood pressure(HBP) measurement in the assessment of antihypertensive effect. Methods: 362 patients onantihypertensive medication performed HBP measurement (5 days, duplicate measurements, four timesdaily) and ambulatory blood pressure (ABP) monitoring in random order. Main outcome measure was theagreement of CBP and HBP with daytime ABP. Results: CBP was much higher than ABP and averageHBP (p < 0.001). There was a progressive decline in HBP over the course of the study, achieving thelevel of daytime ABP on the last 2 monitoring days. The correlation between CBP and ABP was weak(systolic: r = 0.343, diastolic r = 0.430), whereas strong correlations existed between HBP and ABP(systolic r = 0.804, diastolic r = 0.776). A progressive improvement in the strength of the correlationbetween average HBP of single days and ABP was obtained over the 5 monitoring days. The HBPreadings taken in the afternoon showed a stronger correlation with ABP than the values measured in themorning, at noon and in the evening. Averaging more HBP readings taken on succeeding days resulted ina progressive improvement in the agreement with ABP with a further benefit when readings of day 1 wereincluded. Conclusions: The accuracy of telemedical HBP measurement is substantially better than that ofCBP. The results suggest, that HBP should be measured for 5 days, and afternoon measurements shouldbe preferred in assessing control of hypertension.

A comparison of home measurement and ambulatory monitoring of blood pressure in the adjustment of antihypertensive treatment

See related article, pp 1081–1086 The growing worldwide epidemic of high blood pressure in both developed and developing nations is a challenge on many levels.1 The need for better prevention of cardiovascular disease through control of hypertension is clear.2 Public awareness of the need to treat hypertension is partly reflected by the widespread purchases of home blood pressure devices in several of the developed countries. In the United States, Japan, and Finland, the estimates are that 55% to 75% of hypertensive patients already have a home device.3 Research studies have provided a robust epidemiological basis for supporting the greater accuracy of home blood pressure monitoring (HBPM) compared with clinic pressures for prognosis of fatal and nonfatal cardiovascular disease in long-term follow-up surveys and in cross-sectional designs.4 There is a general consensus that HBPM is more convenient, available, and less costly than ambulatory blood pressure monitoring, but the superiority of ambulatory blood pressure monitoring for special clinical problems (ie, detection of nondippers or need for sleep pressures in chronic renal disease, autonomic neuropathies, and sleep apnea) is also clearly recognized.5 Surveys of both physicians6 and patients7 suggest that HBPM is both appreciated and recognized as a valuable strategy. Several experts in the field of hypertension research and care have published appeals to expand the use of HPBM for routine care and to have it supported by health care …

Background: A number of studies reveal that home blood pressure variability is associated with cardiovascular risk factors. However, we do not have a consensus regarding the variability index and the frequency of measurements. Objective: The aim of the study was to assess home blood pressure variability for a period of 7 consecutive days and 24-hour ambulatory blood pressure variability using the average real variability index and to test whether home blood pressure variability represents a suitable parameter for long-term monitoring of the hypertensive patients. Material and methods: A number of 31 hypertensive patients were included in the study, 8 male, 23 female, mean age 60.19±7.35 years. At the inclusion ambulatory blood pressure monitoring was performed, home blood pressure monitoring was carried out for 7 consecutive days with 2 measurements daily. We compared ambulatory blood pressure values, variability using paired t-test. We were looking for correlations between HBP values and cardiovascular risk factors. Results: Ambulatory versus home blood pressure derived mean blood pressure was 131.38±15.2 versus 131.93±8.25, p=0.81. Ambulatory derived variability was 10.65±2.05 versus home variability 10.56±4.83, p=0.91. Home versus ambulatory pulse pressure was 51.8± 9.06 mmHg vs. 54.9±11.9 mmHg, p=0.046. We found positive correlation between HBPV and home BP values, p=0.027, r2=0.1577, (CI: 0.04967 to 0.6588). Home, as well as ambulatory derived variability were positively correlated to age p=0.043, r2=0.1377 (CI: 0.01234 to 0.6451) versus p&lt;0.0001, CI: 0.3870 to 0.8220, r2=0.4302. Conclusion: Assessment of home blood pressure monitoring and variability could represent a well-tolerated alternative for long-term follow-up of hypertension management.

To the Editor: There is growing evidence that blood pressure (BP) monitoring and home BP monitoring are useful for predicting hypertensive target organ damage and the risk of cardio- and cerebrovascular events. Ambulatory BP monitoring and home BP monitoring have been reported to be better predictors than clinic BP in many population studies. In a recent issue of Hypertension , Hara et al showed that ambulatory BP, especially nighttime BP, was better correlated with silent cerebrovascular disease than home BP and that home BP was better associated with carotid atherosclerosis …

Hypertension among people with chronic kidney disease (CKD) is an established risk factor for acceleration of atherosclerotic cardiovascular disease and progression of kidney injury to end-stage renal disease (ESRD).1, 2 Randomized trials have demonstrated that blood pressure (BP)-lowering is translated into a profound benefit on cardiovascular and kidney outcomes.1 However, the optimal levels at which BP should be targeted remains an area surrounded by substantial controversy that is reflected by the discrepancy in BP target recommendations for patients with CKD across guidelines released during 2012-2018 (Table 1). The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guideline recommended a lower BP target of <130/80 mmHg only for CKD patients with persistent albuminuria [defined as albuminuria ≥30 mg/24-h or urinary-albumin-to-creatinine-ratio (UACR) ≥30 mg/g in a random urine specimen].2 In contrast, the 2014 guideline released by the eighth Joint National Committee (JNC8) did not differentiate the BP targets by the level of albuminuria. There was a uniform recommendation to lower BP to levels <140/90 mmHg regardless of the level of kidney function or UACR.5 The controversy was further magnified in more recent guidelines released after the publication of the Systolic Blood Pressure Intervention Trial (SPRINT).6 This landmark trial was prematurely terminated because of an impressive cardiovascular benefit with a lower (<120 mmHg) vs a standard (<140 mmHg) systolic BP (SBP) target in non-diabetic patients with clinic BP ≥ 130/80 mmHg and a high cardiovascular risk profile. Based on the results of SPRINT, the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guideline reappraised the definition of hypertension and recommended a lower BP target of <130/80 mmHg for all patients at high cardiovascular risk, including those with CKD.4 The European Society of Hypertension/European Society of Cardiology (ESH/ESC) did not follow the same approach. In their 2018 guideline, the recommendation for patients with CKD was to lower SBP within the range of 130-139 mmHg and to individualize the intensity of treatment based on its tolerability.3 In this article, we explore the above-described heterogeneity across recent guidelines, providing a critical evaluation of randomized trials that compared a lower vs a standard BP target among patients with CKD. We raise the issue of research-grade BP monitoring method that was implemented in SPRINT and we ask the question whether the impressive results of this trial can be translated into benefit for our patients when intensification of antihypertensive therapy is guided by routine clinic BP recordings. The effect of intensive BP-lowering on kidney outcomes was explored in three separate randomized trials that enrolled non-diabetic patients with CKD (Table 2). The Modification of Diet in Renal Disease (MDRD) followed a 2 × 2 factorial design and randomized 840 patients with GFR 13-55 mL/min/1.73 m2 to two different levels of dietary protein intake and to achieve a lower mean BP (MBP) of <92 mmHg (approximately <125/75 mmHg) vs a standard MBP of 102-107 mmHg (approximately 135/85-140/90 mmHg).7 Over a 2.2-year-long follow-up, the rate of GFR decline did not differ between the lower- and standard-MBP arms. Intensive BP-lowering did not improve the combined outcome of ESRD or death [relative risk (RR): 0.85; 95% confidence interval (CI): 0.60-1.22].7 In the African American Study of Kidney Disease and Hypertension (AASK), 1094 African Americans with hypertensive nephrosclerosis were randomized to a lower vs a standard MBP target (<92 mmHg vs 102-107 mmHg) and to initiate antihypertensive therapy with metoprolol (50-200 mg/d), ramipril (2.5-10 mg/d), or amlodipine (5-10 mg/d) in a 2 × 3 factorial design.8 Over a follow-up of 3-6.4 years, compared with the standard MBP target, intensive BP-lowering had no benefit on the combined outcome of ≥50% decline in GFR, ESRD, or death (risk reduction: 2%; 95% CI: −22% to 21%).8 In the Ramipril Efficacy in Nephropathy trial 2 (REIN-2), 338 patients with non-diabetic, proteinuric CKD already treated with ramipril (2.5-5 mg/d) were randomized to intensified BP-lowering (goal BP <130/80 mmHg) or to standard BP control (diastolic BP <90 mmHg).9 Add-on therapy with felodipine (5-10 mg/d) was administered to achieve the assigned BP targets. REIN-2 was prematurely terminated at a median follow-up of 19 months due to futility. The risk of ESRD was similar in the intensive- and standard-BP groups (HR: 1.00; 95% CI: 0.61-1.64).9 Thus, during their randomized phase, none of these three trials showed that intensive BP-lowering is an effective strategy to halt the progression of kidney injury to ESRD. Post hoc analyses of the MDRD and AASK trials, however, support the notion that the level of proteinuria may act as treatment effect modifier. When MDRD participants were stratified into subgroups by the level of proteinuria at baseline, intensive BP-lowering was associated with a slower rate of GFR decline during follow-up in those with baseline proteinuria of 1-3 g/d or >3g/d. In the proteinuria stratum of <1 g/d, the rate of GFR decline did not differ between the lower- and standard-MBP arms.7 After the completion of the trial phase of AASK, participants were inserted into a cohort phase during which their BP was targeted to levels <130/80 mmHg. Over the entire follow-up of 9.1 years (trial plus cohort phase), the composite outcome of doubling of serum creatinine, ESRD, or death did not differ between those initially randomized to the lower vs those initially randomized to the standard MBP target (HR: 0.91; 95% CI: 0.77-1.08).11 However, there was a significant interaction between the randomized arm and level of baseline proteinuria for the composite kidney outcome (P = .02 for the interaction). In those with proteinuria >0.22 g/d, initial randomization to the lower BP target was associated with 27% reduction in the composite kidney outcome (HR: 0.73; 95% CI: 0.58-0.93). This benefit was not evident in those with baseline proteinuria ≤0.22 g/d (HR: 1.18; 95% CI: 0.93-1.50).11 Another post hoc analysis incorporating data from 840 MDRD participants with an extended follow-up of 9.2 years (trial plus cohort phase) showed that compared with the standard BP target, those initially randomized to intensive BP-lowering had 32% reduced risk of developing ESRD (HR: 0.68; 95% CI: 0.57-0.82).12 Based on this evidence, the 2012 KDIGO guideline recommended a lower BP target of <130/80 mmHg for CKD patients with persistent albuminuria.2 It has to be noted, however, that the strength of this recommendation was labeled as level 2 and the quality of evidence supporting this guidance was graded as level C. This guidance was based mainly on low-quality evidence from the aforementioned post hoc analyses of the MDRD and AASK trials. The observational nature of this data cannot demonstrate direct cause-and-effect associations. This scientific basis was considered insufficient/weak to mandate a reappraisal of BP targets for CKD patients in JNC8.5 Thus, the discrepancy between these two guidelines is not so large. In our interpretation, a level 2C recommendation by the 2012 KDIGO guideline is a clear recognition of the gap in the existing evidence and a call for future research. The effect of intensive BP-lowering on cardiovascular morbidity and all-cause mortality was evaluated in a prespecified post hoc analysis of 2,646 SPRINT participants with eGFR of 20-59 mL/min/1.73 m2.10 The separation between the intensive- and standard-arm was an average difference of −12.3 mmHg in SBP levels. Intensively treated participants required on average ~1 additional antihypertensive medication to achieve the assigned SBP target. This post hoc analysis showed the absence of interaction between the randomized arm and the level of eGFR at baseline for the primary cardiovascular outcome of SPRINT (P ≥ .30 for the interaction). The occurrence of the primary cardiovascular outcome did not differ between the intensive- and standard-arm (HR: 0.81; 95% CI: 0.63-1.05),10 possibly because this post hoc analysis was underpowered to detect a significant between-arm difference in the subgroup of SPRINT participants with eGFR <60 mL/min/1.73 m2. However, intensive BP-lowering provoked a significant 28% reduction in the risk of all-cause death (HR: 0.72; 95% CI: 0.53-0.99).10 Intensive BP-lowering in this post hoc analysis of SPRINT had no benefit on the composite kidney outcome of ≥50% decline in eGFR or ESRD (HR: 0.90; 95% CI: 0.44-1.83).10 Notably, this composite kidney outcome occurred in only 15 participants in the intensive-arm and in 16 participants in the standard-arm. This low incidence rate is not surprising, since patients with proteinuria >1 g/d who would presumably carry a higher risk of kidney injury progression were excluded from SPRINT. Although this trial was not originally designed to assess the efficacy of intensive BP-lowering on kidney outcomes like MDRD and AASK, the results of SPRINT were interpreted as a proof of the cardioprotective benefit of this strategy and provided the scientific basis to recommend a lower BP target of <130/80 mmHg for patients with CKD in the 2017 AHA/ACC guideline.4 The same clinical-trial evidence was interpreted differentially by the 2018 ESH/ESC guideline3 and the question that arises is whether the more conservative approach of European hypertension specialists is reasonable and evidence-based. Of note, the 2018 ESH/ESC guideline3 provided a more conservative recommendation on BP targets particularly for patients with CKD and not for other patient populations. Whether this differentiation is attributable to issues related to the tolerability of intensive BP-lowering in the CKD setting (ie, higher prosperity of these patients to adverse events, higher risk of acute kidney injury episodes, etch) or to other reasons remains another area of uncertainty. The diagnostic accuracy, reproducibility, and predictive value of BP recordings taken at the environment of clinic should be interpreted within the context of the actual methodology implemented (such as, type of BP monitor, the seated rest period before BP measurement, the presence of observer, the number of BP recordings).13 In SPRINT, clinic BP was measured with a fully automated oscillometric device that obtained triplicate recordings after a 5-minute seated rest and often without the presence of observer.6 This research-grade BP monitoring technique differs substantially from routine clinic BP recordings. A meta-analysis of 31 diagnostic-test studies (incorporating data from 9279 participants) showed that fully automated clinic SBP was similar with the reference-standard ambulatory daytime SBP [mean difference (MD): 0.3 mmHg; 95% CI: −1.1 to 1.7 mmHg].14 In contrast, routine clinic SBP overestimated ambulatory daytime SBP by 14.5 mmHg (MD: 14.5 mmHg; 95% CI: 11.8-17.2 mmHg).14 The importance of standardization in BP measurement methodology was highlighted by another meta-analysis of 10 diagnostic-test studies showing that unattended recordings were similar with attended clinic BP recordings, when the same device and measurement methodology was implemented.15 These meta-analyses, however, quantified only the average differences between BP monitoring techniques and did not explore their actual levels of agreement. In a diagnostic-test study that included 275 patients with stage 3-4 CKD and clinic BP <140/90 mmHg, participants underwent clinic BP monitoring with the research-grade technique that was implemented in SPRINT. On the same day, participants had their clinic BP recorded without specification of a 5-minute seated rest.16 Research-grade clinic SBP was by 12.7 mmHg lower than routine clinic SBP (MD: −12.7 mmHg; 95% CI: −14.7 to −10.7 mmHg) and the 95% levels of agreement between these two techniques were ranging from −46.1 to 20.7 mmHg. Research-grade clinic SBP underestimated the reference-standard ambulatory daytime SBP by 7.9 mmHg (MD: −7.9 mmHg; 95% CI: −9.4 to −6.4 mmHg), whereas the 95% levels of agreement were once again wide and were ranging from −33.2 to 17.4 mmHg. Whereas fully automated clinic SBP and ambulatory daytime SBP were significantly associated with echocardiographically documented left ventricular hypertrophy, routine clinic SBP could not detect evidence of target-organ damage.16 Taken together, the above evidence from diagnostic-test studies suggests that the differentiation in recommended BP targets between the American and European guidelines may be simply the tip of the iceberg. Guideline groups have taken into consideration the above-described variability between research-grade and routine clinic BP recordings. Recognizing that the adoption of a research-grade BP monitoring technique like that of SPRINT in daily clinical practice would probably be problematic, the recommended BP targets were adjusted to a higher level from that of the achieved clinic SBP of 121.2 mmHg in the intensive-arm of SPRINT. In our interpretation, a lower or a higher algebraic adjustment for the average bias inserted by routine clinic BP recordings remains an oversimplification.17 An algebraic adjustment for the average differences provides little to no reflection of the actual variability between research-grade and routine clinic BP at the level of individual patients, given the wide 95% levels of agreement between these two techniques in diagnostic-test studies.16 Thus, implementation of intensive BP targets in daily clinical practice necessitates the optimization of our BP measurement methodology. In other words, if antihypertensive therapy continues to be guided by what is already done in routine clinical practice, then intensive BP-lowering may not be beneficial. Evidence to support that intensive BP-lowering to levels <130/80 mmHg is an effective strategy to delay the progression of kidney injury to ESKD is weak. All randomized trials that compared a lower vs a standard BP target in patients with CKD failed to show a benefit of intensive BP-lowering on kidney outcomes.7-9 The notion that intensive BP-lowering is beneficial for those with proteinuric CKD is based on low-quality evidence from post hoc analysis of the MDRD and AASK with an extended observational follow-up after the completion of the randomized phase of these two trials.11, 12 In accordance with the results of MDRD, AASK, and REIN-2, in a post hoc analysis of 2646 SPRINT participants with eGFR <60 mL/min/1.73 m2, intensive BP-lowering did not improve the composite kidney outcome.10 This post hoc analysis, however, provided some evidence to support a potential benefit of intensive BP-lowering on survival and cardiovascular outcomes.10 Even if we interpret this evidence as a proof of cardioprotection, we believe that this benefit may not be generalizable to the majority of our patients if antihypertensive therapy continues to be guided by BP recordings taken under routine clinical practice conditions. In our view, individualization of the intensity of therapy based on its tolerability and optimization of our BP measurement methodology represent important steps to improve BP control and clinical outcomes in this high-risk population. The wider adoption of home or ambulatory BP monitoring is another important step to improve the management of hypertension among patients with CKD. The authors have no conflicts of interest to disclose. Literature search: PIG, VV; Drafting the manuscript: PIG; Revisions on the initial draft: PEZ, VL; Approval of the final paper: VV, VL, PEZ.

Home blood pressure–guided antihypertensive therapy in chronic kidney disease: more data are needed