Maria T. Rios

2013 Ambulatory Blood Pressure Monitoring Recommendations for the Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other Hypertension-associated Risk, and Attainment of Therapeutic Goals

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as “masked normotensives” (elevated clinic BP but normal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “masked hypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of “normotensive” adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).

Administration-Time-Dependent Effects of Hypertension Treatment on Ambulatory Blood Pressure in Patients With Chronic Kidney Disease

Many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in the blood pressure (BP)-lowering efficacy, duration of action, and safety of most classes of hypertension medications. Most important, it was recently documented that routine ingestion of the full daily dose of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Nocturnal hypertension and non-dipping (<10% decline in the asleep relative to the awake BP mean), as determined by ambulatory BP monitoring (ABPM), are frequent in chronic kidney disease (CKD) and both are associated with increased CVD risk. Here, we investigated the influence of hypertension treatment time on the circadian BP pattern and degree of BP control of hypertensive patients with CKD evaluated by 48-h ABPM. This cross-sectional study evaluated 2659 such patients (1585 men/1074 women), 64.9 ± 13.2 (mean ± SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM; 1446 were ingesting all BP-lowering medications upon awakening, whereas 1213 patients were ingesting ≥1 medications at bedtime. Among the latter, 359 patients were ingesting all medications at bedtime, whereas 854 were ingesting the full daily dose of some medications upon awakening and the others at bedtime. Those ingesting all medications upon awakening had significantly higher total cholesterol and low-density lipoprotein (LDL) cholesterol than those ingesting ≥1 medications at bedtime. Moreover, patients ingesting all medications at bedtime had the lowest fasting glucose, serum creatinine, and uric acid. Ingestion of ≥1 medications at bedtime was significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than treatment with all medications upon awakening. The sleep-time relative SBP decline was significantly attenuated in patients ingesting all medications upon awakening (p < .001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.3%) than when ≥1 of them was ingested at bedtime (54.2%; p < .001 between groups), and even further attenuated (47.9%) when all of them were ingested at bedtime (p < .001). Additionally, the prevalence of a riser BP pattern, associated with highest CVD risk, was much greater (21.5%) among patients ingesting all medications upon awakening, compared with those ingesting some (15.7%) or all medications at bedtime (10.6%; p < .001 between groups), independent of CKD severity (disease stage). The latter group also showed a significantly higher prevalence of properly controlled ambulatory BP (p < .001) that was achieved by a significantly lower number of hypertension medications (p < .001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, in patients with CKD ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for CKD. (Author correspondence: rhermida@uvigo.es)

Treatment-Time Regimen of Hypertension Medications Significantly Affects Ambulatory Blood Pressure and Clinical Characteristics of Patients With Resistant Hypertension

Patients with resistant hypertension (RH) are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom blood pressure (BP) is responsive to and well controlled by therapeutic interventions. Although all chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice daily (BID) is frequent. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of RH patients evaluated by 48-h ambulatory BP monitoring (ABPM). This cross-sectional study evaluated 2899 such patients (1701 men/1198 women), 64.2 ± 11.8 (mean ± SD) yrs of age, enrolled in the Hygia Project. Among the participants, 1084 were ingesting all hypertension medications upon awakening (upon-awakening regimen), 1436 patients were ingesting the full daily dose of ≥1 of them at bedtime (bedtime regimen), and 379 were ingesting split doses of ≥1 medications BID upon awakening and at bedtime (BID regimen). Patients of the bedtime regimen compared with the other two treatment-time regimens had lower likelihood of microalbuminuria and chronic kidney disease; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; plus higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. The bedtime regimen was also significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the upon-awakening and BID regimens (p < .001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5% and 77.3%, respectively) than in the bedtime regimen (54.4%; p < .001 between groups). Additionally, the prevalence of the riser BP pattern, associated with highest CVD risk, was much greater, 31.0% and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared with the bedtime regimen (17.6%; p < .001 between groups). Patients of the bedtime regimen also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) as a result of a greater proportion of them showing complete control of asleep SBP and DBP means. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in RH patients ingesting the full daily dose of ≥1 hypertension medications at bedtime than in those ingesting all of them upon awakening or ≥1 of them as split doses BID. In RH, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered chronotherapy. Collectively, findings of this study indicate that a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of true RH and avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for patients who, by conventional cuff methods (and in the absence of ABPM) and the morning-treatment regimen, have been mistakenly judged to be resistant to therapy. (Author correspondence: rhermida@uvigo.es)

Prevalence and Clinical Characteristics of Isolated-Office and True Resistant Hypertension Determined by Ambulatory Blood Pressure Monitoring

Hypertension is defined as resistant to treatment when a therapeutic plan including ≥3 hypertension medications failed to sufficiently lower systolic (SBP) and diastolic (DBP) blood pressures (BPs). Most individuals, including those under hypertension therapy, show a “white-coat” effect that could cause an overestimation of their real BP. The prevalence and clinical characteristics of “white-coat” or isolated-office resistant hypertension (RH) has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ambulatory monitoring (ABPM), therefore including patients with either normal or elevated asleep BP mean. Here, we investigated the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated cardiovascular (CVD) risk of isolated-office RH. This cross-sectional study evaluated 3042 patients treated with ≥3 hypertension medications and evaluated by 48-h ABPM (1707 men/1335 women), 64.2 ± 11.6 (mean ± SD) yrs of age, enrolled in the Hygia Project. Among the participants, 522 (17.2%) had true isolated-office RH (elevated clinic BP and controlled awake and asleep ambulatory BPs while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office RH (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP mean while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true RH (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ≥4 medications). Patients with false, relative to those with true, isolated-office RH had higher prevalence of microalbuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (p < .001), significantly higher 48-h SBP/DBP means by 9.6/5.3 mm Hg (p < .001), significantly lower sleep-time relative SBP and DBP decline (p < .001), and significantly greater prevalence of a non-dipper BP profile (96.9% vs. 38.9%; p < .001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4% vs. 5.0% (p < .001), among patients with false isolated-office RH. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, chronic kidney disease, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared with those with true isolated-office RH (2.13 [95% confidence interval: 1.95–2.32]; p < .001). Patients with false isolated-office hypertension and true RH, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, microalbuminuria, and chronic kidney disease, and they had an equivalent estimated hazard ratio of CVD events (1.04 [95% confidence interval: .97–1.12]; p = .265). Our findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office RH and true RH, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true RH plus a nonsignificant increased CVD risk of this condition compared with isolated-office RH are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of RH patients into categories of isolated-office RH, masked RH, and true RH cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of nighttime BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true RH. (Author correspondence: rhermida@uvigo.es)

Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9 ± 10.6 (mean ± SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p < .001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p < .001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p < .001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p < .001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) that was achieved by a significantly lower number of hypertension medications (p < .001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)

Chronotherapy improves blood pressure control and reduces vascular risk in CKD

In patients with chronic kidney disease (CKD), the prevalence of increased blood pressure during sleep and blunted sleep-time-relative blood pressure decline (a nondipper pattern) is very high and increases substantially with disease severity. Elevated blood pressure during sleep is the major criterion for the diagnoses of hypertension and inadequate therapeutic ambulatory blood pressure control in these patients. Substantial, clinically meaningful ingestion-time-dependent differences in the safety, efficacy, duration of action and/or effects on the 24 h blood pressure pattern of six different classes of hypertension medications and their combinations have been substantiated. For example, bedtime ingestion of angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers is more effective than morning ingestion in reducing blood pressure during sleep and converting the 24 h blood pressure profile into a dipper pattern. We have identified a progressive reduction in blood pressure during sleep—a novel therapeutic target best achieved by ingestion of one or more hypertension medications at bedtime—as the most significant predictor of decreased cardiovascular risk in patients with and without CKD. Recent findings suggest that in patients with CKD, ambulatory blood pressure monitoring should be used for the diagnosis of hypertension and assessment of cardiovascular disease risk, and that therapeutic strategies given at bedtime rather than on awakening are preferable for the management of hypertension.

Chronotherapeutics of conventional blood pressure-lowering medications: simple, low-cost means of improving management and treatment outcomes of hypertensive-related disorders.

Correlation between blood pressure (BP) target organ damage, cardiovascular risk, and long-term prognosis is greater for ambulatory monitored (ABPM) than daytime in-clinic measurements. Additionally, consistent evidence of numerous studies substantiates the ABPM-determined asleep BP mean is an independent and stronger predictor of risk and incidence of end-organ injury and cardiovascular events than the awake or 24-h means. Hence, cost-effective control of sleep-time BP is of great clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of six different classes and their combinations significantly impacts beneficial and/or adverse effects. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers better controls the asleep than awake BP means, with additional benefit independent of terminal half-life of converting the 24-h BP profile into more normal dipper patterning. Recent findings authenticate therapeutic reduction of sleep-time BP, best achieved when the full daily dose of ≥1 hypertension medications is routinely ingested at bedtime, is the most significant independent predictor of lowered cardiovascular and cerebrovascular risk.

Abnormalities in chronic kidney disease of ambulatory blood pressure 24 h patterning and normalization by bedtime hypertension chronotherapy

In chronic kidney disease (CKD), the prevalence of hypertension is very high, escalating with diminishing renal function. Typically, the diagnosis of hypertension and the clinical decisions regarding its treatment are based on daytime clinic blood pressure (BP) measurements. However, the correlation between BP level and target organ damage, cardiovascular risk and long-term prognosis is greater for ambulatory than clinic measurements. Moreover, evidence is consistent among numerous studies that the elevated risk and incidence of end-organ injury and fatal and non-fatal cardiovascular events are significantly associated with blunted night-time BP decline, and that the asleep BP better predicts cardiovascular events than either the awake or 24-h BP mean. The prevalence of abnormally high asleep BP is extensive in CKD, significantly increasing with its severity. In CKD, the diagnoses of hypertension and its therapeutic control are often inaccurate in the absence of complete and careful assessment of the entire 24 h, i.e. daytime and night-time, BP pattern. Accordingly, ambulatory BP monitoring should be the preferred method to comprehensively assess and decide the optimal clinical management of patients with CKD. Recent findings indicate therapeutic restoration of normal physiologic BP reduction during night-time sleep is the most significant independent predictor of decreased cardiovascular and cerebrovascular risk, both in patients with and without CKD, and is best achieved when antihypertensive medications, mainly those blocking the renin-angiotensin-aldosterone system, are routinely taken at bedtime.

Around-the-clock Ambulatory Blood Pressure Monitoring is Required to Properly Diagnose Resistant Hypertension and Assess Associated Vascular Risk

Diagnosis of resistant hypertension (RH) is currently based upon awake-time office blood pressure (BP). An increasing number of studies have documented abnormally elevated sleep-time BP in most RH patients, indicating that diagnosis of true RH cannot be determined solely by comparison of office BP with either patient awake-time BP self-measurements or awake-BP mean from ambulatory monitoring (ABPM), as is customary in the published literature. Moreover, the ABPM-determined sleep-time BP mean is an independent and stronger predictor of cardiovascular and cerebrovascular disease (CVD) risk than either daytime office/ABPM-derived awake or 24-hour means. Results of the recently completed MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares) prospective outcomes study, which included a large cohort of RH patients, established that time of treatment relative to circadian rhythms constituted a critically important yet often neglected variable with respect to BP control. The study found that bedtime versus morning ingestion of the full dose of ≥1 BP-lowering medications resulted in both better therapeutic normalization of sleep-time BP and reduced CVD morbidity and mortality, including in RH patients. Accordingly, ABPM is highly recommended to properly diagnose and manage true RH, with a bedtime hypertension medication regimen as the therapeutic scheme of choice.

Bedtime Blood Pressure Chronotherapy Significantly Improves Hypertension Management

Consistent evidence of numerous studies substantiates the asleep blood pressure (BP) mean derived from ambulatory BP monitoring (ABPM) is both an independent and a stronger predictor of cardiovascular disease (CVD) risk than are daytime clinic BP measurements or the ABPM-determined awake or 24-hour BP means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of 6 different classes and their combinations significantly improves BP control, particularly sleep-time BP, and reduces adverse effects.