Z. Kobalava

The effects of amlodipine and enalapril on renal function in adults with hypertension and nondiabetic nephropathies: A 3-year, randomized, multicenter, double-blind, placebo-controlled study

BACKGROUND Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome. OBJECTIVE The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d). METHODS Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (<1 and >or=1 g/d) before unblinding the database. RESULTS Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria >1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P<0.001) but not in patients taking amlodipine plus diuretics (-25 mg/d at last observation). CONCLUSION In this cohort of nondiabetic, nonnephrotic hypertensive patients, no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers, including in the subgroup of patients with proteinuria >1 g/d.

Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

Summary Aims Concomitant renin–angiotensin–aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF. Methods This was an open‐label, noncontrolled single‐sequence study. After a 24‐h run‐in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II–IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin‐converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]). Results On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio‐to‐baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P < 0.05). Plasma NT‐proBNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin‐1 levels significantly decreased on Day 21 (all, P < 0.05). Following administration of LCZ696, the Cmax of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100‐ and 200‐mg doses, the Cmax and AUC 0–12 h for sacubitril and LBQ657 were approximately dose‐proportional while that of valsartan was less than dose‐proportional. Conclusions Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study.

AIMS Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg(-1)  day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.

Effects of Hepatic Impairment on the Pharmacokinetics of Everolimus: A Single-Dose, Open-Label, Parallel-Group Study

BACKGROUND Although the pharmacokinetics of everolimus, an oral mammalian target of rapamycin inhibitor, have been characterized in patients with moderate hepatic impairment, they have not been assessed in those with mild or severe hepatic impairment. OBJECTIVE The goal of this study was to assess the pharmacokinetics and safety of everolimus in healthy volunteers with normal hepatic function and patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment in otherwise good health to inform dosing in the clinical setting. METHODS A multicenter, open-label, Phase I study in which all enrollees received a single, 10-mg, oral everolimus dose was conducted. Blood samples for pharmacokinetic assessment were collected at predetermined time points up to 168 hours postdosing. Safety was also assessed. Proposed dose recommendations based on Child-Pugh status at baseline and day 8 were calculated based on AUC0-∞ geometric mean ratios and their associated 90% CIs. Post hoc analysis of the relationship between pharmacokinetic parameters and markers of hepatic function was also performed to identify thresholds for dose adjustment. RESULTS Thirteen subjects with normal hepatic function and 7 patients with mild, 8 patients with moderate, and 6 patients with severe hepatic impairment were enrolled. Compared with normal subjects, everolimus AUC0-∞ for patients with mild, moderate, and severe hepatic impairment increased by 1.60-, 3.26-, and 3.64-fold, respectively. Based on Child-Pugh classification at day 8, the everolimus doses required to adjust the exposure of patients with mild, moderate, and severe hepatic impairment to that of normal subjects were 6.25, 3.07, and 2.75 mg, respectively. Thresholds for 2-fold everolimus dose reduction were 15.0 μmol/L for bilirubin, 43.1 g/L for albumin, and 1.1 for the international normalized ratio; using these thresholds could lead to underdosing or overdosing in some patients. Most adverse events were of grade 1 severity, ≤1 day in duration, and not everolimus related. CONCLUSIONS Everolimus exposure after a single 10-mg dose was influenced by the degree of hepatic impairment. Child-Pugh classification was found to be the most conservative means of guiding dose adjustment in patients with hepatic impairment. Based on these data, as well as previously reported data for patients with moderate hepatic impairment, everolimus once-daily dosing should be 7.5 mg and 5 mg in patients with mild and moderate impairment, respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case, 2.5 mg once daily should not be exceeded. ClinicalTrials.gov identifier: NCT00968591.

Validation of TM-2655 oscillometric device for blood pressure measurement.

ObjectiveTo perform validation for an arm-type oscillometric TM-2655 device (A&D Company Ltd, Tokyo, Japan) for blood pressure measurement according to the British Hypertension Society protocol. MethodsEighty-five study participants (33 men and 52 women) were included in the study. Mean age was 52.9±15.0 years, systolic blood pressure range was 84–208 mmHg and diastolic blood pressure range was 48–120 mmHg. For each participant, three readings of TM-2655 were compared with sequential auscultatory measurements by two trained independent observers. The observers used a calibrated mercury sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. ResultsThe average difference between mercury sphygmomanometer and TM-2655 readings for systolic blood pressure was −1.0+5.2 mmHg (mean±SD) and for diastolic blood pressure −0.9±4.7 mmHg. The proportions of values agreeing to within 5, 10 and 15 mmHg were 72.5, 93.7 and 99.6% for systolic blood pressure and 78.8, 96.9 and 100% for diastolic blood pressure between the observers and the device (A/A British Hypertension Society grade). ConclusionsThe TM-2655 device achieved British Hypertension Society grade A/A and therefore can be recommended for blood pressure measurement in an adult population.

Validation of the integration of technology that measures additional "vascular" indices into an ambulatory blood pressure monitoring system

Background The objective of this study was to validate the novel integration of oscillometric (Vasotens®) technology into a BPLab® ambulatory blood pressure (BP) monitoring system to measure central BP, the aortic augmentation index, and pulse wave velocity (PWV) compared with the recommended and widely accepted tonometric method. Methods The ARTERY Society guidelines for comparison of PWV measurement techniques were used as the basis for recruitment of 99 individuals (mean age 44±19 years, 52 males). The standard for comparison was the conventional “classic” SphygmoCor device. Results Accordance of the two methods was satisfactory (r=0.98, mean difference of 2.9±3.5 mmHg for central systolic BP; r=0.98, mean difference of −1.1±2.3 mmHg for central diastolic BP; r=0.83, mean difference of −2.6%±13% for aortic augmentation index; r=0.85, mean difference of 0.69±1.4 for PWV). Conclusion The performance of Vasotens algorithms using an oscillometric ambulatory BP monitoring system is feasible for accurate diagnosis, risk assessment, and evaluation of the effects of antihypertensive drugs.

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome. Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3 ± 10.7 years, mean BP: 158.8 ± 14.2/93.4 ± 10.0 mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5 mg OD. BP control was defined as <140/90 mmHg for all patients and <130/80 mmHg for those with diabetes mellitus or chronic nephropathy. Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8 ± 9.7/80.5 ± 6.9 mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n = 477), 74.8% of those with diabetes (n = 214), 75.6% of those with chronic nephropathy (n = 82), and 85.1% of patients with metabolic syndrome (n = 745). No case of hypokalemia was reported. Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.

Validation of semi-automatic device UA-704 for self-measurement of blood pressure.

ObjectiveTo perform a clinical validation for a semi-automatic arm-type device UA-704 (A&D Company, Ltd., Tokyo, Japan) according to the British Hypertension Society protocol. MethodsEighty-five study participants (37 men) were included. The mean age was 50.1±17.0 years, systolic blood pressure range was 79–212 mmHg and diastolic blood pressure range was 43–118 mmHg. For each participant, three readings of the UA-704 were compared with simultaneous auscultatory measurements by two trained independent observers. The observers used a mercury calibrated sphygmomanometer and a dual stethoscope. The results were graded according to the 1993 British Hypertension Society protocol. ResultsThe average difference between mercury sphygmomanometer and UA-704 readings was −1.85±4.26 mmHg (mean±SD) for systolic blood pressure and −1.44±3.97 mmHg for diastolic blood pressure. The proportions of values agreeing to within 5, 10 and 15 mmHg were 79.2%, 96.5% and 99.6% for systolic blood pressure and 86.7%, 96.9% and 99.6% for diastolic blood pressure for the observers and device (A/A grade for British Hypertension Society). ConclusionsFor an adult population, the UA-704 device for self-measurement of blood pressure achieved a British Hypertension Society grade A/A and therefore can be recommended for home blood pressure monitoring.

SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES.

The burden of cardiovascular diseases (CVD) in general and heart failure (HF) in particular continues to increase worldwide. CVD are major contributors to death and morbidity and recognized as important drivers of healthcare expenditure. Chronic overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in human hypertension and HF pathophysiology. RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of hormones, which regulate vascular tone, and specifically blood pressure through vasoconstriction and renal sodium and water retention. Drugs inhibiting key components of the RAAS have become a cornerstone of contemporary cardiovascular drug therapy. Nowadays there is a high priority for the development of innovative therapeutic agents that better control blood pressure, have a therapeutic potential in HF and enhance current therapies for CVD. The enhancement of the biological activities of the natriuretic peptides (NP) via inhibition of their degradation is one of the novel strategies.Natriuretic peptide system includes primarily three well-characterized peptides with structural similarity: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These three peptides are involved in the maintenance of cardio-renal homeostasis and all have cardio-renal protective properties. Atrial natriuretic peptide and BNP are synthetized mainly by the cardiomyocytes in response to cardiac stretch, whereas CNP is mainly produced by endothelial cells in response to cytokines and endothelium-dependent agonists. B-type natriuretic peptide is also produced by cardiofibroblasts where it elicits its antifibrotic actions in the heart. All NP function via the second messenger cGMP. All three peptides are cleared by the clearance receptor (NPR-C), not linked to a guanylate cyclase. The NP are also cleared from the circulation via enzymatic degradation by neutral endopeptidase (NEP). Natriuretic peptides play key role in the regulation of electrolytes and water balance homeostasis, blood pressure levels through diuretic, natriuretic, vasorelaxant effects, along with the ability to inhibit the RAAS and the sympathetic nervous system. They modulate systemic vascular resistance by inhibiting the contraction of vascular smooth muscle cells through cGMP-dependent kinases. Apart from increased volume overload and myocytes stress hormonal stimuli are involved in the control of NP release.Besides hemodynamic functions, new properties of NP have been recently discovered related to the interaction with cellular growth and proliferation at the vascular level. Natriuretic peptides preserve vascular health in endothelial and vascular smooth muscle cells by interfering with the key mechanisms of atherosclerosis (proliferation, angiogenesis, apoptosis, and inflammation). Natriuretic peptides exert antihypertrophic and antifibrotic actions within the heart.There is a growing body of evidence that dysregulation of the NP system exists in CVD. Hypertension and HF are considered as NP deficiency state. During the evolution of HF the heart increases its production and release of ANP and BNP in order to compensate the increased water retention. Elevated circulating levels of such hormones have been associated with worsening of HF and poor prognosis. Recent studies have reported that in patients with congestive HF and high plasma BNP levels there is actually a lack of mature BNP. Studies have confirmed that altered processing of BNP occurs in HF and hence a relative deficiency of this protective hormone. The presence of shorter, less biologically active precursors and multiple degraded forms of BNP was also demonstrated. These data explain the blunting of the expected physiological responses to apparently high levels of BNP. Patients with advanced HF may actually be in a state of NP deficiency.Similar to HF, patients with essential hypertension may also have NP deficiency state. Studies suggested that a deficiency of bioactive BNP may be present in the early stages of hypertension thus favoring its progression. It was revealed that BNP system was not activated and ANP system was lower in pre-hypertensives than in normotensive subjects. Altered processing pathway of pro-BNP to mature BNP also occurs in hypertension. This impaired processing of the NP may result in reduced blood pressure-lowering effects of NP and leads to hypertension progression, more severe CVD and overt HF. Besides single-nucleotide polymorphisms of the ANP and BNP gene as well as the NP clearance receptor have been identified.In summary there is the existence of a deficiency state of biologically active cardiac NP in hypertension and HF. As a result of their cardiovascular properties NP are currently viewed as active players in the process of cardiovascular remodeling and in the natural history of hypertension and HF. Manipulation of this system is a logical pursuit and represents a new therapeutic opportunity for CVD. Current NP-augmenting strategies include the design of a number of synthetic NP and inhibition of neprilysin.A key component of the NP system is the NEP (neprilysin). This membrane-bound metallopeptidase is widely expressed, but is most abundant in the kidney. Neprilysin serves as the principal mechanism for enzymatic removal of the native NPs with susceptibility to degradation greatest for CNP>ANP>BNP. Importantly, many other substrates for neprilysin exist, some of them with opposing physiological actions. These include endothelin-1, kinin peptides, opioid peptides, substance P, amyloid beta protein, gastrin. Neprilysin also hydrolyzes angiotensin-I to angiotensin-(1-7). Inhibition of NEP (NEPi) has been advanced as a potential therapeutic modality. NEP inhibition alone leads to an increase in circulating levels of both vasodilators as well as vasoconstrictors. Neutral endopeptidases ability to degrade multiple substrates means that the sole NEPi yields broader effects than anticipated and explains why NEPi is best combined with the inhibition of other vasoactive compounds. Angiotensin receptor blockers (ARB) do not disrupt bradykinin metabolism as much as ACE-inhibitors, and some patients with ACE-inhibitor-associated angioedema can be switched over to an ARB without the occurrence of angioedema. A novel class of drugs that combines the actions of NEP inhibitors and ARB, known as angiotensin receptor blockade with neutral endopeptidase inhibition (ARNi) was developed. LCZ696 is the first compound of this category. Novel ARNi-based therapeutic strategies are expected contribute to optimize control of CVD and of their outcomes.

AchievemenT of target resting HEart rate on beta-blockers in patients with stable angiNA and hypertension (ATHENA) in routine clinical practice in Russia

Abstract Objectives: The primary objective of this study was to establish the proportion of patients with stable angina and arterial hypertension on beta-blocker (BB) treatment reaching target resting heart rates (RHR) of 55–60 beats per min in clinical cardiology and general practice in Russia. Secondary objectives included the association between achievement of target RHR and mean BB doses, Seattle Angina Questionnaire (SAQ) scores and achievement of target blood pressure (BP) levels (systolic/diastolic BP <140/90 mmHg). Research design and methods: ATHENA (AchievemenT of target resting HEart rate on beta-blockers in patients with stable angiNA and hypertension) was a non-interventional, cross-sectional, observational study conducted in 20 sites in Russia (NCT01321242). The study population comprised patients aged ≥18 years with stable angina (class I–III) and primary hypertension, on BB treatment for ≥2 months prior to enrollment. Results: Of 399 study participants, 62 (15.5%; 95% confidence interval [CI]: 0.121 to 0.195) achieved target RHR. Clinical characteristics associated with significant differences between subgroups achieving and not achieving target RHR were systolic BP (131.1 vs 138.2 mmHg, P = 0.006), diastolic BP (78.6 vs 83.5 mmHg, P < 0.001) and frequency of nitroglycerin administration (1.5% vs 3.0%, P = 0.045). Most patients were taking bisoprolol (48.9%) and metoprolol (36.1%), with mean daily doses of 5.5 mg and 73.7 mg, respectively. Median SAQ scores were: 52.8 physical limitation, 50.0 angina stability, 60.0 angina frequency, 75.0 treatment satisfaction, 50.0 disease perception (quality of life) and 59.6 total score, with no significant differences between subgroups. Patients achieving target RHR were significantly more likely also to achieve target BP, compared with patients not achieving target RHR (72.6% vs 53.4%; P = 0.005; odds ratio: 2.309; 95% CI: 1.270 to 4.197). Conclusion: In a Russian population with stable angina and hypertension on BB treatment, RHR control was suboptimal. ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT01321242.