Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial.

AIMS: The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction. METHODS AND RESULTS: In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)]. CONCLUSION: Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00741585.

Does Timing of Antihypertensive Medication Dosing Matter?

PURPOSE OF REVIEW: Current hypertension guidelines do not provide recommendation on when-to-treat. Herein, we review the current evidence on ingestion-time differences of hypertension medications in blood pressure (BP)-lowering effects and prevention of cardiovascular disease (CVD) events. RECENT FINDINGS: The vast (81.6%) majority of the 136 published short-term treatment-time trials document benefits, including enhanced reduction of asleep BP and increased sleep-time relative BP decline (dipping), when hypertension medications and their combinations are ingested before sleep rather than upon waking. Long-term outcome trials further document bedtime hypertension therapy markedly reduces risk of major CVD events. The inability of the very small 18.4% of the published trials to substantiate treatment-time difference in effects is mostly explained by deficiencies of study design and conduct. Our comprehensive review of the published literature reveals no single study has reported better benefits of the still conventional, yet scientifically unjustified, morning than bedtime hypertension treatment scheme.

Characterization of triple-negative breast cancer preclinical models provides functional evidence of metastatic progression.

Triple-negative breast cancer (TNBC), an aggressive, metastatic and recurrent breast cancer (BC) subtype, currently suffers from a lack of adequately described spontaneously metastatic preclinical models that faithfully reproduce the clinical scenario. We describe two preclinical spontaneously metastatic TNBC orthotopic murine models for the development of advanced therapeutics: an immunodeficient human MDA-MB-231-Luc model and an immunocompetent mouse 4T1 model. Furthermore, we provide a broad range of multifactorial analysis for both models that could provide relevant information for the development of new therapies and diagnostic tools. Our comparisons uncovered differential growth rates, stromal arrangements and metabolic profiles in primary tumors, and the presence of cancer-associated adipocyte infiltration in the MDA-MB-231-Luc model. Histopathological studies highlighted the more rapid metastatic spread to the lungs in the 4T1 model following a lymphatic route, while we observed both homogeneous (MDA-MB-231-Luc) and heterogeneous (4T1) metastatic spread to axillary lymph nodes. We encountered unique metabolomic signatures in each model, including crucial amino acids and cell membrane components. Hematological analysis demonstrated severe leukemoid and lymphoid reactions in the 4T1 model with the partial reestablishment of immune responses in the immunocompromised MDA-MB-231-Luc model. Additionally, we discovered ß-immunoglobulinemia and increased basal levels of G-CSF correlating with a metastatic switch, with G-CSF also promoting extramedullary hematopoiesis (both models) and causing hepatosplenomegaly (4T1 model). Overall, we believe that the characterization of these preclinical models will foster the development of advanced therapeutic strategies for TNBC treatment, especially for the treatment of patients presenting both, primary tumors and metastatic spread.

Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention.

Aims: Sleep-time blood pressure (BP) is a stronger risk factor for cardiovascular disease (CVD) events than awake and 24 h BP means, but the potential role of asleep BP as therapeutic target for diminishing CVD risk is uncertain. We investigated whether CVD risk reduction is most associated with progressive decrease of either office or ambulatory awake or asleep BP mean. Methods and results: We prospectively evaluated 18 078 individuals with baseline ambulatory BP ranging from normotension to hypertension. At inclusion and at scheduled visits (mainly annually) during follow-up, ambulatory BP was measured for 48 consecutive hours. During the 5.1-year median follow-up, 2311 individuals had events, including 1209 experiencing the primary outcome (composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke). The asleep systolic blood pressure (SBP) mean was the most significant BP-derived risk factor for the primary outcome [hazard ratio 1.29 (95% CI) 1.22-1.35 per SD elevation, P < 0.001], regardless of office [1.03 (0.97-1.09), P = 0.32], and awake SBP [1.02 (0.94-1.10), P = 0.68]. Most important, the progressive attenuation of asleep SBP was the most significant marker of event-free survival [0.75 (95% CI 0.69-0.82) per SD decrease, P < 0.001], regardless of changes in office [1.07 (0.97-1.17), P = 0.18], or awake SBP mean [0.96 (0.85-1.08), P = 0.47] during follow-up. Conclusion: Asleep SBP is the most significant BP-derived risk factor for CVD events. Furthermore, treatment-induced decrease of asleep, but not awake SBP, a novel hypertension therapeutic target requiring periodic patient evaluation by ambulatory monitoring, is associated with significantly lower risk for CVD morbidity and mortality.

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.

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.

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.

Elevated asleep blood pressure and non-dipper 24h patterning best predict risk for heart failure that can be averted by bedtime hypertension chronotherapy: A review of the published literature.

Several prospective studies consistently report elevated asleep blood pressure (BP) and blunted sleep-time relative systolic BP (SBP) decline (non-dipping) are jointly the most significant prognostic markers of cardiovascular disease (CVD) risk, including heart failure (HF); therefore, they, rather than office BP measurements (OBPM) and ambulatory awake and 24 h BP means, seemingly are the most worthy therapeutic targets for prevention. Published studies of the 24 h BP pattern in HF are sparse in number and of limited sample size. They report high prevalence of the abnormal non-dipper/riser 24 h SBP patterning. Despite the established clinical relevance of the asleep BP, past as do present hypertension guidelines recommend the diagnosis of hypertension rely on OBPM and, when around-the-clock ambulatory BP monitoring (ABPM) is conducted to confirm the elevated OBPM, either on the derived 24 h or "daytime" BP means. Additionally, hypertension guidelines do not advise the time-of-day when BP-lowering medications should be ingested, in spite of known ingestion-time differences in their pharmacokinetics and pharmacodynamics. Between 1976 and 2020, 155 unique trials of ingestion-time differences in the effects of 37 different single and 14 dual-combination hypertension medications, collectively involving 23,972 patients, were published. The vast majority (83.9%) of them found the at-bedtime/evening in comparison to upon-waking/morning treatment schedule resulted in more greatly enhanced: (i) reduction of asleep BP mean without induced sleep-time hypotension; (ii) reduction of the prevalence of the higher CVD risk non-dipper/riser 24 h BP phenotypes; (iii) improvement of kidney function, reduction of cardiac pathology, and with lower incidence of adverse effects. Most notably, no single published randomized trial found significantly better BP-lowering, particularly during sleep, or medical benefits of the most popular upon-waking/morning hypertension treatment-time scheme. Additionally, prospective outcome trials have substantiated that the bedtime relative to the upon-waking, ingestion of BP-lowering medications not only significantly reduces risk of HF but also improves overall CVD event-free survival time.

Cardiovascular disease risk stratification by the Framigham score is markedly improved by ambulatory compared with office blood pressure.

INTRODUCTION AND OBJECTIVES: Ambulatory blood pressure (BP) better predicts cardiovascular disease (CVD) outcomes than office BP measurements (OBPM). Nonetheless, current CVD risk stratification models continue to rely on exclusively daytime OBPM along with traditional factors, eg, age, sex, smoking, dyslipidemia, and/or diabetes. METHODS: Data from 19 949 participants of the primary care-based Hygia Project assessed by 48-hour ambulatory BP monitoring (ABPM) and without prior CVD events were used to compare the diagnostic accuracy, discrimination, and performance of the original Framingham risk score (RSOFG) and its adjusted version to the Hygia Project study population (RSAFG) with that of a novel CVD risk stratification model constructed by replacing OBPM with ABPM-derived prognostic parameters (RSABPM). RESULTS: During the follow-up, lasting up to 12.7 years, 1854 participants experienced a primary CVD outcome of CVD death, myocardial infarction, coronary revascularization, heart failure, stroke, transient ischemic attack, angina pectoris, or peripheral artery disease. Asleep systolic BP (SBP) mean and sleep-time relative SBP decline were the only joint significant ABPM-derived predictive factors of CVD risk and were therefore used to substitute for in-clinic SBP in the RSABPM model. The RSABPM model, in comparison with the RSOFG and RSAFG models, showed significantly improved calibration, diagnostic accuracy, discrimination, and performance (always P<.001). The RSAFG-derived event-probabilities of 57.3% of the participants were outside the 95% confidence limits of the event probability determined by the RSABPM model. CONCLUSIONS: These collective findings reveal important limitations of CVD risk stratification when based upon OBPM, as in the Framingham score, and corroborate the clinical value of around-the-clock ABPM to properly diagnose true hypertension and reliably stratify CVD vulnerability.

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.

Ambulatory blood pressure monitoring-based definition of true arterial hypertension.

Daytime office blood pressure measurements (OBPM), still recommended and utilized today for diagnosis and management of hypertension and categorization of cardiovascular disease (CVD) risk, fail to reveal clinically important features of the mostly predictable BP 24 h pattern and leads to a large proportion of individuals being misclassified. Most clinical guidelines now recommend ambulatory BP monitoring (ABPM) be applied to adult patients to confirm the OBPM-based diagnosis of hypertension, based on the high prevalence of masked hypertension and masked normotension plus demonstrated significantly better CVD prognostic value of around-the-clock ABPM than daytime OBPM. Nonetheless, there is yet no consensus of which parameter(s) and ABPM thresholds to utilize to diagnose hypertension. Findings of large prospective ABPM-based CVD outcome trials permit prospective evaluation of treatment and other induced changes in OBPM and ABPM during follow-up on CVD risk by incorporating multiple periodic (at least annual) patient ABPM assessments. They indicate: 1) asleep systolic BP (SBP) mean and sleep-time relative SBP decline (dipping) together are the most significant and only BP-derived prognostic markers of CVD risk; accordingly, around-the-clock ABPM should be the recommended method to diagnose true arterial hypertension and accurately assess CVD risk; and (2) treatment-induced lowering of the asleep SBP mean and rise of the sleep-time relative SBP decline towards the normal dipper BP pattern are both significantly protective against CVD events, thus constituting novel therapeutic targets to substantially better reduce CVD risk compared to the traditional approach that targets control of daytime OBPM or awake BP mean.

New perspectives on the definition, diagnosis, and treatment of true arterial hypertension.

INTRODUCTION: Office blood pressure measurements (OBPM), still used today for diagnosis and management of hypertension, fail to reveal clinically important features of the mostly predictable blood pressure (BP) 24 h pattern, and lead to >45% of individuals being misclassified. Current hypertension guidelines do not provide recommendation on when-to-treat, despite multiple prospective clinical trials documenting improved normalization of 24 h BP pattern and significant reduction in cardiovascular disease (CVD) events when hypertension medications are ingested at bedtime rather than upon waking. AREAS COVERED: In this review, the authors discuss current evidence on the: (i) most relevant attributes of the 24 h BP pattern deterministic of CVD risk; (ii) asleep systolic BP (SBP) mean as the most significant therapeutic target for CVD risk reduction; (iii) ingestion-time differences in pharmacodynamics of BP-lowering medications as reported with high consistency in multiple clinical trials; and (iv) enhanced prevention of CVD events achieved by bedtime hypertension chronotherapy. EXPERT OPINION: Several prospective trials consistently document asleep SBP mean and sleep-time relative SBP decline (dipping) constitute highly significant CVD risk factors, independent of OBPM. Bedtime, compared to customary upon-waking, hypertension chronotherapy reduces risk of major CVD events. Collectively, these findings call for new definition of true hypertension and, accordingly, its proper diagnosis and management.

The Hygia Project and Hygia Chronotherapy Trial: insights of we clinical investigators on the impact of the embedded continuing medical education on primary-care practice and improved patient cardiovascular health.

The participating doctors of the Hygia Chronotherapy Trial (HCT) are aware of the criticisms of its published findings, which have been unjustifiably misrepresented in letters to the editors and commentaries, perhaps because of lack of understanding of the foundations of the Hygia Project, in which the HCT is nested. Thus, our purpose through this communication is to highlight the unique features of the Hygia Project and HCT in terms of: (i) organization, management, and quality control, (ii) physician training/continuing medical education, and (iii) impact on every-day primary-care clinical practice specifically improved patient care through 48 h ambulatory blood pressure monitoring to diagnose and optimally manage by bedtime hypertension chronotherapy true arterial hypertension to markedly improve the cardiovascular health of our patients.

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as corroborated by the Hygia Chronotherapy Trial. Rebuttal to European Society of Hypertension officials.

Reinhold Kreutz and colleagues in a recent editorial claim the Hygia Chronotherapy Trial lacks credibility because of deficient methods, thereby dismissing both the plausibility and clinical significance of its reported findings. They misstate and misrepresent crucial information, findings and conclusions unambiguously detailed in the published report of the Hygia Chronotherapy Trial. The purpose of this communication is to provide a complete rebuttal to each and every one of the misleading and scientifically unsupported claims by Kreutz et al. that calls into question their expertise to decry the merits, advantages, limitations and validity of correctly designed and conducted ambulatory blood pressure monitoring-based chronotherapy trials.

Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment.

The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of -omics-based analysis to accelerate anticancer DDS.

Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models.

Metabolomics is becoming a relevant tool for understanding the molecular mechanisms involved in the response to new drug delivery systems. The applicability of this experimental approach to cell cultures and animal models makes metabolomics a useful tool for establishing direct connections between in vitro and in vivo data, thus providing a reliable platform for the characterization of chemotherapeutic agents. Herein, we used metabolomic profiles based on nuclear magnetic resonance (NMR) spectroscopy to evaluate the biochemical pathways involved in the response to a chemotherapeutic anthracycline drug (Doxorubicin, Dox) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-conjugated form (HPMA-Dox) in an in vitro cell culture model and an in vivo orthotopic breast cancer model. We also used protein expression and flow cytometry studies to obtain a better coverage of the biochemical alterations associated with the administration of these compounds. The overall analysis revealed that polymer conjugation leads to increased apoptosis, reduced glycolysis, and reduced levels of phospholipids when compared to the free chemotherapeutic drug. Our results represent a first step in the application of integrated in vitro and in vivo metabolomic studies to the evaluation of drug delivery systems.

Capturing "Extraordinary" Soft-Assembled Charge-Like Polypeptides as a Strategy for Nanocarrier Design.

The rational design of nanomedicines is a challenging task given the complex architectures required for the construction of nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Herein, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in nonsalty aqueous solutions is identified, which matches the ubiquitous "ordinary-extraordinary" phenomenon previously described by physicists. For the first time, a bottom-up methodology for the stabilization of these nanosized soft-assembled star-shaped polyglutamates is also described, enabling the translation of theoretical research into nanomaterials with applicability within the drug-delivery field. Covalent capture of these labile assemblies provides access to unprecedented architectures to be used as nanocarriers. The enhanced in vitro and in vivo properties of these novel nanoconstructs as drug-delivery systems highlight the potential of this approach for tumor-localized as well as lymphotropic delivery.

Influence of age and hypertension treatment-time on ambulatory blood pressure in hypertensive patients.

Some studies based on ambulatory blood pressure (BP) monitoring (ABPM) have reported a reduction in sleep-time relative BP decline towards a more non-dipping pattern in the elderly, but rarely have past studies included a proper comparison with younger subjects, and no previous report has evaluated the potential role of hypertension treatment time on nighttime BP regulation in the elderly. Accordingly, we evaluated the influence of age and time-of-day of hypertension treatment on the circadian BP pattern assessed by 48-h ABPM. This cross-sectional study involved 6147 hypertensive patients (3108 men/3039 women), 54.0 ± 13.7 (mean ± SD) yrs of age, with 2137 (978 men/1159 women) being ≥60 yrs of age. At the time of study, 1809 patients were newly diagnosed and untreated, and 4338 were treated with hypertension medications. Among the later, 2641 ingested all their prescribed BP-lowering medications upon awakening, whereas 1697 ingested the full daily dose of ≥1 hypertension medications at bedtime. Diagnosis of hypertension in untreated patients was based on ABPM criteria, specifically an awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85 mm Hg and/or an asleep SBP/DBP mean ≥120/70 mm Hg. Collectively, older in comparison with younger patients were more likely to have diagnoses of microalbuminuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, anemia, and/or obesity. In addition, the group of older vs. younger patients had higher glucose, creatinine, uric acid, triglycerides, and fibrinogen, but lower cholesterol, hemoglobin, and estimated glomerular filtration rate. In older compared with younger patients, ambulatory SBP was significantly higher and DBP significantly lower (p < .001), mainly during the hours of nighttime sleep and initial hours after morning awakening. The prevalence of non-dipping was significantly higher in older than younger patients (63.1% vs. 41.1%; p < .001). The largest difference between the age groups was in the prevalence of a riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 4.9% in older vs. younger patients, respectively; p < .001). The sleep-time relative SBP decline was mainly unchanged until ~40 yrs of age, and then significantly and progressively decreasing with increasing age at a rate of .28%/yr (p < .001), reaching a minimum value of 4.38% ± .47% for patients ≥75 yrs of age. Treated compared with untreated patients showed lower awake and asleep SBP means, although the predictable changes of SBP and DBP with age were equivalent in both groups. As a consequence, there were no significant differences between untreated and treated patients in the changes of the sleep-time relative SBP and DBP declines with age. Additionally, the asleep SBP and DBP means were significantly lower and the sleep-time relative SBP and DBP declines significantly higher at all ages in patients ingesting ≥1 BP-lowering medications at bedtime as compared with those ingesting all medications upon awakening. Our findings document a significantly elevated prevalence of a blunted nighttime BP decline with increasing age ≥40 yrs. The prevalence of a riser BP pattern, associated with highest cardiovascular risk among all possible BP patterns, was 4 times more prevalent in patients ≥60 yrs of age than those <60 yr of age. Most important, there was an attenuated prevalence of a blunted nighttime BP decline at all ages when ≥1 hypertension medications were ingested at bedtime as compared with when all of them were ingested upon awakening. These findings indicate that older age should be included among the conditions for which ABPM is recommended for proper cardiovascular risk assessment.