Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions.

This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body.

Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials.

Combined evidence of published prospective outcome trials and meta-analyses substantiate elevated asleep blood pressure (BP) and blunted sleep-time relative BP decline (non-dipping), regardless of wake-time office BP and awake or 24 h BP means, are jointly the most highly significant independent prognostic markers of cardiovascular disease (CVD) risk and worthy therapeutic targets for prevention. Nonetheless, current guidelines continue to recommend the diagnosis of hypertension, when based on ambulatory BP monitoring (ABPM), rely, solely, on either the 24 h or "daytime" BP means. They also fail to recommend the time to treat patients.

Ingestion-time differences in the pharmacodynamics of hypertension medications: Systematic review of human chronopharmacology trials.

Pharmacokinetics of hypertension medications is significantly affected by circadian rhythms that influence absorption, distribution, metabolism and elimination. Furthermore, their pharmacodynamics is affected by ingestion-time differences in kinetics and circadian rhythms comprising the biological mechanism of the 24 h blood pressure (BP) pattern. However, hypertension guidelines do not recommend the time to treat patients with medications.

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.

Chronotherapy of cardiac and vascular disease: timing medications to circadian rhythms to optimize treatment effects and outcomes.

Circadian rhythms impact cardiac and vascular pathophysiology, resulting in 24-hour patterning of symptoms and life-threatening/ending events (chronopathology), plus kinetics and dynamics of medications (chronopharmacology), resulting in administration-time differences in efficacy and safety. Scheduling medications according to circadian rhythm determinants (chronotherapy) can improve treatment effects, for example, before dinner/bedtime ingestion of cholesterol-lowering medications and acetylsalicylic acid, respectively, exerts enhanced control of hypercholesterolemia and after-awakening peak of platelet aggregation; bedtime ingestion of conventional hypertension medications optimizes normalization of sleep-time blood pressure (BP)-strongest independent BP marker of cardiovascular disease (CVD) risk-and most effectively prevents (chronoprevention) CVD morbidity and mortality. Exploration of chronotherapeutic strategies to improve management of cardiac arrhythmias and vascular pathophysiology is still awaited.

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 (RS) and its adjusted version to the Hygia Project study population (RS) with that of a novel CVD risk stratification model constructed by replacing OBPM with ABPM-derived prognostic parameters (RS).

Ingestion-time - relative to circadian rhythms - differences in the pharmacokinetics and pharmacodynamics of hypertension medications.

Introduction: Hypertension guidelines do not recommend the time to administer blood pressure (BP)-lowering medications, despite multiple prospective clinical trials reporting both improved normalization of BP 24 h patterning and reduced cardiovascular disease (CVD) events when ingested at bedtime rather than upon awakening.

Areas Covered: We review: (i) circadian rhythm-dependent influences on the pharmacokinetics (PK) and pharmacodynamics (PD) of hypertension medications; (ii) reports of ingestion-time differences in PK and PD of such therapies; and (iii) (chrono)prevention of CVD morbidity and mortality achieved by the simple and low-cost bedtime hypertension chronotherapy strategy, i.e.

Ambulatory blood pressure-based inclusion criteria in the Hygia Chronotherapy Trial. Rebuttal to Lemmer and Middeke.

The purpose of this communication is to respond to the continuing invalid criticism by Lemmer and Middeke of the MAPEC and Hygia Chronotherapy Trial by emphasizing the: (i) already unambiguously reported ambulatory blood pressure monitoring (ABPM)-based definition of hypertension utilized as inclusion criterion of both investigations and (ii) impact of bedtime hypertension chronotherapy on ABPM-assessed parameters and cardiovascular disease (CVD) outcome for participants further categorized by influential markers of CVD risk. In so doing, we call attention to apparent unethical misconduct of Lemmer and Middeke of multiple duplicated publications of the very same unfounded criticisms.

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.

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.

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.

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as documented by MAPEC and Hygia Chronotherapy outcomes trials.

The purpose of this communication is to describe the unique features of the investigative protocols of both MAPEC and Hygia Chronotherapy Trial and to discuss in detail the advantages, limitations, and potential implications of their findings, both for the diagnosis and management of true arterial hypertension that we propose must be defined according to ambulatory blood pressure monitoring (ABPM)-based criteria. In particular, the recommended approach for diagnosis and follow-up of hypertension derived from the findings of MAPEC and Hygia Chronotherapy Trial entails baseline 48-h ABPM assessment for both proper diagnosis of true arterial hypertension and establishment of the eventual need of therapeutic intervention, plus follow-up by periodic 48-h ABPM assessment, specifically for evaluation of timed treatment efficacy and safety.

Current evidence on the circadian-time-dependent effects of hypertension medications and their combinations in relation to findings of MAPEC and Hygia Chronotherapy Trial.

The main purpose of this commentary is to update, based on our extensive review of the published literature of the past 45 yrs, the differential therapeutic effects of hypertension medications of various classes and their combinations when ingested in the evening/at-bedtime versus in the morning/upon-awakening. Interestingly, revision of the currently available evidence on the differential circadian-time-dependent effects of hypertension medications of six different classes and their combinations indicates among the 137 published hypertension medication trials that evaluated blood pressure (BP)-lowering efficacy according to treatment-time, 112 (81.75%) documented significant better benefits by evening/bedtime compared to morning/awakening-scheduled therapy.

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.

Chronotherapy for reduction of cardiovascular risk.

Numerous prospective studies establish that elevated asleep blood pressure (BP) constitutes a significant cardiovascular disease (CVD) risk factor, irrespective of daytime office BP measurements or awake and 24h BP measurements. Moreover, except for a small number of studies with flawed methodology, multiple clinical trials of high consistency document significantly better BP-lowering efficacy of hypertension medication and their combinations when ingested at bedtime compared to upon awakening as is customary. Additionally, recent trials conclude bedtime hypertension chronotherapy markedly reduces CVD risk not only in the general population, but also in more vulnerable patients of advanced age, with kidney disease, diabetes, or resistant hypertension.

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.

Diagnosis and management of hypertension: around-the-clock ambulatory blood pressure monitoring is substantially more effective and less costly than daytime office blood pressure measurements.

The cost-effectiveness of ambulatory blood pressure (BP) monitoring (ABPM) versus traditional office BP measurement (OBPM) for the diagnosis and management of hypertension has been evaluated only by few studies and based solely on the reduction of medical care expenses through avoiding treatment of isolated-office hypertension. Data from the 21963 participants in the Hygia Project, a multicenter outcomes study that incorporates into routine primary care periodic, at least yearly, 48 h ABPM evaluation, were utilized to assess the cost-effectiveness - relative to vascular pathology expenditures countrywide in Spain - of ABPM versus OBPM. The actual reported Spanish healthcare expenditure for vascular pathology in 2015 - aggregate costs of medical examinations, outpatient and inpatient care, therapeutic interventions, plus non-healthcare services (productivity losses due to morbidity/mortality and informal family/friends-provided care) - was used to compare yearly costs when diagnostic and treatment decisions for hypertension are based on the OBPM versus the ABPM-model.