Elevated blood pressure (BP) is the leading cause of cardiovascular disease and a major contributor to mortality, affecting almost one third of the adult population worldwide. Despite strong scientific evidence, guidelines and multiple therapeutic options, many patients remain undertreated or uncontrolled, largely due to poor medication adherence and medical inertia. Complexity of multi-pill regimens contributes significantly to non-adherence, whereas single-pill combinations (SPCs) improve adherence and persistence, accelerate BP control, and promote better long-term outcomes than multiple combinations. Appropriate selection of SPC in individual hypertensive patients may be a difficult though very important task for physicians. Thus, development of tools that may facilitate use of SPC in clinical practice is desirable. Among renin-angiotensin system blockers, olmesartan (OM) has demonstrated sustained efficacy, favourable tolerability, both as monotherapy and in SPCs with amlodipine and/or hydrochlorothiazide, which are available in multiple dosages. The present OM-based platform builds on earlier frameworks and incorporates guidelines' updates complemented by a systematic review of available literature. This "3.0" proposal expands patient categorization to include comorbidities or complications often overlooked in clinical practice guidelines, providing a practical, evidence-based approach to support individualized hypertension management complementing guideline recommendations.

Drug-excipient incompatibility in solid oral dosage forms can generate toxic degradants and compromise potency without producing a visible macroscopic signal in early development. We reported, for the first time, a mechanistically resolved, temperature-sequenced characterization of the solid-state acid-base incompatibility between amlodipine besylate (AMLO; pKa ≈ 9.4) and citric acid (CA; pKa1 3.13; ΔpKa = 6.27) using six orthogonal techniques: DSC, TGA, isothermal titration calorimetry (ITC), powder X-ray diffractometry with two-dimensional correlation spectroscopy (2D-COS-PXR), FTIR with 2D-COS (2D-COS-FTIR), and stability-indicating HPLC coupled to LC-QToF HRMS. Binary mixtures were thermally stressed at 40-90 °C (7 day isothermal, closed-vial). ITC confirmed a spontaneous, entropy-dominated interaction (ΔG = -5.14 kcal/mol; -TΔS = -3.78 kcal/mol; N ≈ 1:1; KD = 197 μM) driven by proton transfer to the AMLO dihydropyridine nitrogen with concurrent besylate displacement. DSC showed complete loss of the AMLO Form-I endotherm (onset 201.01 °C), replaced by a single event at 155.57 °C with super-additive enthalpy (+19.50 J/g), consistent with amlodipine citrate salt formation. Application of Noda's 2D-COS algorithm to temperature-resolved PXRD and FTIR datasets independently resolved a four-stage mechanism, viz., CA surface proton mobilization (40 °C) → amlodipine citrate nucleation (50-60 °C) → besylate counter-ion displacement and d-spacing contraction (∼70 °C) and → partial amorphization and acid-catalyzed covalent degradation (80-90 °C). Three sequential-order reversals in the 2D-COS-FTIR asynchronous map independently corroborated the Stage-3 crystallographic sequence. HPLC revealed a 4.48-fold enhancement of AMLO loss in the mixture (7.97%) versus pure drug (1.78%), with LC-QToF HRMS identifying four mixture-unique degradants consistent with the four-stage model. This is also the first pharmaceutical application of 2D-COS-PXRD as a mechanistic probe of sequential crystallographic events in drug-excipient incompatibility.

Elderly patients with concurrent coronary artery disease (CAD) and hypertension face elevated risks of cardiovascular events and require therapies that balance efficacy, safety, and tolerability. Sacubitril/valsartan has demonstrated benefits in heart failure management, but evidence regarding its long-term cardiovascular outcomes in this specific population remains limited. This retrospective cohort study enrolled 150 elderly patients with CAD and hypertension to compare the effects of sacubitril/valsartan versus amlodipine, both combined with conventional therapy. The primary endpoint was the incidence of major adverse cardiovascular events (MACE) over 12 months. Two MACE definitions were applied in this study. Primary analysis used our predefined composite endpoint, including aggravated heart failure and arrhythmia events. A sensitivity analysis adopted the conventional MACE definition (myocardial infarction, stroke, cardiovascular death, revascularization), excluding isolated ventricular premature beats. Secondary endpoints included blood pressure control, cardiac function parameters, and treatment-related adverse events. Results showed that patients treated with sacubitril/valsartan had a significantly lower incidence of MACE (10.26% vs. 27.14%, P = 0.008), superior blood pressure control, and improved left ventricular ejection fraction (LVEF) compared to the amlodipine group. Cox proportional hazards regression (Cox regression) analysis identified sacubitril/valsartan treatment as an independent protective factor against cardiovascular adverse events (hazard ratio (HR) = 0.38, 95% confidence interval (CI): 0.18-0.80, P = 0.011). Both regimens were well-tolerated, with no severe adverse events reported. These findings indicate that sacubitril/valsartan is an effective and safe therapeutic option for elderly patients with CAD and hypertension, reducing long-term cardiovascular risk while improving blood pressure control and cardiac function.

A conservative BCS class III classification was recently proposed for amlodipine based on inconclusive permeability evidence. However, the scarce in vivo data suggest that amlodipine is slowly, though completely, absorbed. This means that the very rapid dissolution criterion associated with a BCS class III classification may be overly restrictive for immediate-release amlodipine products. The aim of this manuscript was to develop and validate a physiologically based biopharmaceutics model (PBBM) to assess the risk of bioequivalence failure associated with dissolution. Given that amlodipine is a lipophilic weak base, the absorption model incorporated a surrogate representation of intracellular lysosomal trapping through the FuEnt parameter, resulting in an adequate description of oral pharmacokinetics. Dissolution input included in vitro profiles obtained in phosphate buffer pH 6.8 at 50 rpm for different multisource products, fitted to either the Johnson model or the Z-factor approach. Although several products did not meet biowaiver dissolution criteria, virtual bioequivalence simulations conducted with the validated PBBM consistently predicted bioequivalence across tested formulations. Overall, these findings suggest that dissolution differences would have limited impact on the in vivo performance of amlodipine and support a low dissolution-related bioequivalence risk for immediate-release amlodipine tablets.

This predefined subgroup analysis of the ESCORT-HT study evaluated the antihypertensive efficacy, organ-protective effects, and safety profile of esaxerenone compared with an angiotensin II receptor blocker (ARB) in patients aged ≥65 years with hypertension on amlodipine, stratified by the presence or absence of type 2 diabetes mellitus (T2DM). In the T2DM subgroup, 65 patients received esaxerenone and 55 received an ARB. In the non-T2DM subgroup, 135 and 145 patients received these treatments, respectively. The least squares mean change from baseline at the end of treatment in morning home systolic blood pressure in the T2DM subgroup was -10.9 (95% confidence interval -13.5, -8.4) mmHg in esaxerenone-treated patients and -8.8 (-11.5, -6.0) mmHg in ARB-treated patients; in the non-T2DM subgroup, these were -10.5 (-12.3, -8.7) mmHg and -9.1 (-10.8, -7.3) mmHg, respectively. Although this subgroup analysis was not powered to formally demonstrate non-inferiority, the between-treatment differences in morning home SBP were consistent with the non-inferiority of esaxerenone to ARBs based on the margin used in the primary analysis in both the T2DM and non-T2DM subgroups. Urinary albumin-to-creatinine ratio (UACR) significantly decreased in esaxerenone-treated patients with T2DM (-33.4%), but not in those without T2DM. In contrast, UACR significantly decreased in ARB-treated patients without T2DM (-21.2%), but not in those with T2DM. One esaxerenone-treated patient in the non-T2DM subgroup had a serum potassium level ≥6.0 mEq/L, and a low proportion of esaxerenone-treated patients in the non-T2DM subgroup had hypokalemia (2.2%). Overall, this subgroup analysis showed favorable antihypertensive and kidney-protective effects (based on UACR) of esaxerenone, combined with an acceptable safety profile, in patients with hypertension. Moreover, antihypertensive effects were observed regardless of T2DM status, supporting the use of esaxerenone in older patients with hypertension and comorbid T2DM.

The ESCORT-HT study recently demonstrated non-inferiority of esaxerenone to angiotensin II receptor blockers (ARBs) in lowering morning home systolic blood pressure (SBP) in Japanese patients aged ≥65 years with inadequately controlled hypertension on amlodipine. This predefined subgroup analysis of the ESCORT-HT study analyzed age-related differences in the efficacy and safety of esaxerenone relative to ARBs. In the 65-74-year subgroup, 98 patients were treated with esaxerenone and 94 with an ARB; in the ≥75-year subgroup, 104 were treated with esaxerenone and 106 with an ARB. The least squares mean difference in morning home SBP between the two treatment groups at end of treatment was -1.1 (95% confidence interval [CI] -3.8, 1.6) mmHg for the 65-74-year subgroup and -2.2 (95% CI -5.2, 0.9) mmHg for the ≥75-year subgroup. The upper bound of the 95% CI was within the pre-defined non-inferiority margin of <3.8 mmHg. The urine albumin-to-creatinine ratio decreased in all groups at Week 12, regardless of age or treatment, and N-terminal pro-B-type natriuretic peptide levels decreased in esaxerenone-treated patients, regardless of age. The incidence of treatment-emergent adverse events was 34.3% (esaxerenone) and 32.0% (ARB) in patients 65-74 years, and 16.7% and 29.6%, respectively, in patients aged ≥75 years. There were no notable increases in the incidence of hyperkalemia or hypokalemia, relative to ARBs, in any of the age subgroups. This predefined subgroup analysis of the ESCORT-HT study showed antihypertensive effects consistent with the non-inferiority of esaxerenone to ARBs in both age groups, and suggested a potential cardioprotective effect, including for patients aged ≥75 years.