Guidelines-based therapeutic strategies for controlling hypertension in non-controlled hypertensive patients followed by family physicians in primary health care in Portugal: the GPHT-PT study.

PURPOSE: In a prospective open study, with intervention, conducted in Primary Health Care Units by General Practitioners (GPs) in Portugal, the effectiveness of a single pill of candesartan/amlodipine (ARB/amlodipine), as the only anti-hypertension (anti-HTN) medication, in adult patients with uncontrolled HTN (BP > 140/or > 90 mm Hg), either previously being treated with anti-HTN monotherapies (Group I), or combinations with hydrochlorothiazide (HCTZ) (Group II), or not receiving medication at all (Group III), was evaluated across 12-weeks after implementation of the new therapeutic measure. MATERIALS AND METHODS: A total of 118 GPs recruited patients with uncontrolled HTN who met inclusion/exclusion criteria. Participants were assigned, according to severity, one of 3 (morning) fixed combination candesartan/amlodipine dosage (8/5 or 16/5 or 16/10 mg/day) and longitudinally evaluated in 3 visits (v0, v6 and v12 weeks). Office blood pressure was measured in each visit, and control of HTN was defined per guidelines (BP< 140/90 mmHg). RESULTS: Of the 1234 patients approached, 752 (age 61 ± 10 years, 52% women) participated in the study and were assigned to groups according to previous treatment conditions. The 3 groups exhibited a statistically significant increased control of blood pressure after receiving the fixed combination candesartan/amlodipine dosage. The overall proportion of controlled HTN participants increased from 0,8% at v0 to 82% at v12. The mean arterial blood pressure values decreased from SBP= 159.0 (± 13.0) and DBP= 91.1 (± 9.6) at baseline to SBP= 132,1 (± 11.3) and DBP= 77,5 (± 8.8) at 12 weeks (p < 0.01). Results remained consistent when controlling for age and sex. CONCLUSION: In patients with uncontrolled HTN, therapeutic measures in accordance with guidelines, with a fixed combination candesartan/amlodipine, allowed to overall achieve HTN control at 12 weeks in 82% of previously uncontrolled HTN patients, reinforcing the advantages of these strategies in primary clinical practice.

What is the context?Arterial hypertension (HTN) represents the main risk factor for cause of death from cardiovascular disease (CV). Adequate control of hypertension reduces CV risk and significantly prevents CV events and associated morbidity and mortality. This requires patients' adherence and persistence in implemented treatment and the achievement of tension targets that are related to the reduction of CV risk. The latest international recommendations indicate that hypertension control is insufficient in most countries. In Portugal, hypertension control is <43% and a significant number of patients treated do not comply with the recommendations.What is new?In a prospective, interventional, and multicentre study, carried out by General Practitioners (GPs) in Primary Health Care Units across Portugal, the objective was to determine (i) whether the presence of uncontrolled hypertension results from non-compliance with the provisions of the recommendations and the Integrated Care Process (PAI) of the Direção Geral de Saúde (DGS), i.e. inappropriate use of monotherapies or inadequate low doses of combinations of antihypertensives, and (ii) whether the adjustment of hypertension therapies, favouring the schemes provided in the recommendations, allows adequate control of arterial hypertension, in previously uncontrolled patients, when these are closely monitored in a 12-week time period.What is the impact?When the guidelines' therapeutic protocol is followed, as established for each identified group of patients (monotherapy, hydrochlorothiazide, and no medication), results indicate a marked and statistically significant improvements in both SBP and DBP values and hypertension control across time.

Clinical Benefit of Fixed-Dose Combination of Amlodipine and Potent Atorvastatin in Patients With Concomitant Hypertension and Hypercholesterolemia.

BACKGROUND: Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages. METHODS AND RESULTS: Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]). CONCLUSIONS: Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.

Extemporaneous combination therapy with nebivolol/amlodipine for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVE: The investigation of the real-world use of the extemporaneous combination of nebivolol and amlodipine (NA-EXC) in adult patients diagnosed with hypertension in Europe. METHODS: Retrospective analysis of data extracted from seven databases of patient medical records and prescriptions from Italy, Germany, France, Hungary, and Poland, to determine the prevalence and incidence of NA-EXC use and to estimate the number of patients potentially eligible for a single-pill combination of the two antihypertensives. Secondary objectives included: the description of the population of NA-EXC users and the assessment of their adherence to treatment based on the proportion of days covered. RESULTS: The use of NA-EXC was found to be common in Europe and ranged between 2.9% to 9.9% of all patients identified in the databases with a prescription of nebivolol and/or amlodipine. The estimated numbers of patients potentially eligible in 2019 for a single-pill combination of nebivolol and amlodipine in Italy and Germany were, respectively, 178,133 and 113,240. Users of NA-EXC were mostly aged 70-79 years, had metabolic disorders and other comorbidities; >70% of them had received ≥2 concomitant medications before starting NA-EXC. Adherence to NA-EXC was defined as high only in 15.6% to 35% of patients. CONCLUSIONS: The extemporaneous combination of nebivolol and amlodipine is commonly prescribed in Europe, however adherence to the therapy is poor. The development of a single-pill combination of nebivolol and amlodipine may improve adherence by reducing the number of pills administered to patients and thus simplifying treatment regimens.

Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication.

BACKGROUND: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail. METHODS: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes. RESULTS: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill. CONCLUSION: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.

The effects of Olmesartan/amlodipine administered in the Morning or At Night on nocturnal blood pressure reduction in Chinese patients with mild-moderate essential hypertension (OMAN Trial): study protocol for a prospective, multicenter, randomized, open-label clinical trial {1}.

INTRODUCTION: Hypertension increases the risk of cardiovascular disease. Uncontrolled nocturnal blood pressure is prevalent in patients taking antihypertensive medication, with an incidence rate of 30-60%. Although chronotherapy with antihypertensive agents may provide a new direction for effective control of nocturnal blood pressure, the clinical evidence base remains controversial. This research is presently underway to compare the effects of morning and bedtime administration of antihypertensive medication on nocturnal reduction and circadian rhythm of blood pressure in patients with hypertension. METHODS AND ANALYSIS: This study is being performed as a randomized, multicenter, open-label, parallel-group, clinical trial in which 720 participants are to undergo 24-h ambulatory blood pressure measurement (ABPM) and office blood pressure measurement (OBPM) at baseline before being randomly assigned to a morning (6-10 am) or a bedtime (6-10 pm) administration group. Each participant receives one 20/5-mg tablet of olmesartan/amlodipine (OA) daily for 4 weeks and is then followed up at 4-week intervals for a total of 12 weeks. During follow-up, the OA dosage is adjusted according to the ABPM and OBPM results. Patients with uncontrolled hypertension at the first follow-up visit will receive an increase in OA dosage to 1.5 tablets/day. For patients with blood pressure that is still uncontrolled after a further 4 weeks, the dosage of OA can be increased to 2 tablets/day. The primary objective is the reduction in mean nocturnal systolic blood pressure between baseline and week 12. The secondary objectives are the reduction in ambulatory blood pressure at weeks 4 and 12 and the blood pressure control rate at weeks 4, 8, and 12. DISCUSSION: Antihypertensive chronotherapy remains controversial. A superiority test hypothesis design has been adopted for this trial, in which all participants will be taking the same antihypertensive medication. We anticipate that our findings will determine if nocturnal blood pressure control in Chinese patients with essential hypertension varies according to whether antihypertensive medication is taken in the morning or at bedtime. This study may provide scientific evidence for the application of chronotherapy in clinical practice. TRIAL REGISTRATION: ChiCTR2200059719. Registered on 10 May 2022 ( http://www.chictr.org.cn/edit.aspx?pid=169782&htm=4 ) {2a,2b}.

Combinação fixa de benazepril associado a anlodipino para adultos com hipertensão arterial sistêmica com controle inadequado da pressão arterial / Fixed combination of benazepril associated with amlodipine for adults with controlled systemic arterial hypertension inadequate blood pressure

INTRODUÇÃO: A hipertensão arterial sistêmica (HAS), uma doença crônica, é um grave problema de saúde pública, caracterizada por níveis elevados e persistentes da pressão sanguínea, medidos em geral como uma razão da pressão arterial sistólica e diastólica (respectivamente maior ou igual a 140 mmHg; e/ou maior ou igual a 90 mmHg). Esta é uma doença altamente prevalente em todo o mundo. No Brasil, os números podem variar de acordo com a metodologia utilizada. Reportou-se na Pesquisa Nacional de Saúde de 2013, cujos dados são obtidos por autorrelato, a prevalência de hipertensão em 21% dos pacientes, mas ao considerar a aferição da pressão arterial e uso de medicamentos, o percentual de adultos com pressão arterial ≥140/90 mmHg foi de 32%. Sabe-se que a falta de controle da pressão arterial pode elevar o risco de ocorrência de eventos cardiovasculares, como infarto agudo do miocárdio, insuficiência cardíaca, acidente vascular cerebral, doenças renais, entre outros. Isso consequentemente pode causar problemas crônicos que reduzem a qualidade de vida do indivíduo, e até mesmo o

Telmisartan Plus Amlodipine as the Preferred Initial Combination in Newly Diagnosed Indian Patients with Hypertension: An Expert Consensus Statements.

INTRODUCTION: Hypertension (HTN) remains one of the most important risk factors for cardiovascular (CV) diseases and a leading cause of mortality worldwide. Despite improvement in detection and treatment, poor blood pressure (BP) control rates are observed globally. The situation in India is alarming with only 22.5% of patients maintaining their BP under control. Initiating early and effective treatment for HTN helps control BP within normal limits and reduces associated health risks. In India, currently, there are no guidelines on the choice of dual combination treatment that can be considered an initial treatment for newly diagnosed HTN patients to achieve effective BP control and reduce CV risks. OBJECTIVE: To provide consensus recommendations for preferred initial combinations in newly diagnosed Indian patients with HTN. METHODOLOGY: A core group of 100 experts with HTN expertise conceptualized and formulated the four key questions based on answerability, effectiveness, potential for translation to clinical practice, novelty, and potential impact on the healthcare burden. A mix of Delphi and Child Health and Nutrition Research Initiative (CHNRI) methods was adopted for acceptance or refusal of recommendations. Likert scale 1-9 was used for scoring. A score of ≥7 was considered "statement accepted," >6.50 "near to acceptance" and <6.50 "not accepted." A vote of ≥7 by at least two-thirds of the experts (66.66%) was mandatory for acceptance of the recommendation. CONCLUSION: Combination therapy could be necessary for a majority of newly diagnosed Indian patients for effective BP control. It can manage HTN with better clinical outcomes. Based on mean rating scores from experts, telmisartan plus amlodipine can be considered the preferred initial combination in the management of newly diagnosed Indian patients with HTN to achieve better BP control and improve CV outcomes.

Molding as Innovative Technology for Personalized Tablet Production.

The future of dosage form design is expected to move towards the production of personalized dosage forms tailored to each patient. The 3D printer was introduced to solve that problem but is not easy to use in a pharmacy. Herein, a new 3D mold technology is adopted for tablet manufacturing. Preparation of amlodipine tablets was used as a Biopharmaceutics Classification System Class 1 drug model to study this technology. Different concentrations of either starch or Avicel-based formulations and different concentrations of hydroxypropyl methylcellulose as a binder for mass formation were used. The mass formed for each formula was cast into the mold for tablet preparation. Different non-pharmacopeial and pharmacopeial quality-control tests of the prepared tablets by using the 3D mold were compared to a marketed tablet product of amlodipine. 3D-molded tablets showed compliance properties with the tablet pharmacopeial quality standard. Studying the equivalence of the 3D mold tablets to the brand marketed product under biowaiver conditions was carried out. The difference and similarity factors studies of molded tablets prepared using starch or Avicel as a filler and 2.5% of hydroxypropyl methylcellulose showed acceptable characters to the drug brand name. It is predicted that by using this simple technique, it would be possible to produce tablets with designed disintegration and release profiles, which could potentially allow the tailoring of the drug release and hence personalize the medicine for each patient.

Effects of individualized administration of folic acid on prothrombotic state and vascular endothelial function with H-type hypertension: A double-blinded, randomized clinical cohort study.

BACKGROUND: Hypertension and hyperhomocysteinemia (HHcy) have long been associated with adverse cardiovascular and cerebrovascular health outcomes. This study evaluated the effect of individualized administration of folic acid (FA) on homocysteine (Hcy) levels, prothrombotic state, and blood pressure (BP) in patients with H-type hypertension (combination of HHcy and hypertension). METHODS: In this double-blinded, randomized clinical cohort study, 126 patients with H-type hypertension who were treated at our hospital were randomly divided into treatment and control groups (n = 55 each). The control group was treated with oral levamlodipine besylate tablets 2.5 mg and placebo, once a day (in the morning). The treatment group was first treated with oral levamlodipine besylate 2.5 mg and FA tablets 0.8 mg, once a day (in the morning), for 12 weeks. Then, in a second 12-week phase, the FA dose was adjusted using the methylene tetrahydrofolate reductase C677 polymorphism genotype. The levels of Hcy and coagulation factors, prothrombotic state parameters, BP, and adverse drug reactions were compared between the 2 groups. RESULTS: Pretreatment general patient characteristics, including Hcy levels, were similar between the 2 groups (P > .05). BP and prothrombotic status did not differ before and after the first phase of treatment (P > .05). However, Hcy and endothelin-1 (ET-1) levels decreased, while nitric oxide levels increased significantly in the intervention group (P < .05). In the second phase, after 3 months' treatment with an FA dose adjusted according to methylene tetrahydrofolate reductase C677T genotype, the Hcy and ET-1/NO levels were significantly decreased in the intervention group and were lower than those after the first treatment phase and lower than in the control group (P < .01). BP, D-dimer levels, and fibrinogen scores were significantly lower after the second treatment phase (P < .01). There was no significant difference in the incidence of adverse drug reactions between the 2 groups (P > .05). CONCLUSIONS: Individualized administration of FA tablets can effectively reduce BP, and Hcy and coagulation factor levels, and significantly improve prothrombotic status in patients with H-type hypertension.

Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.

BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.

Effect of Co-Administration of Curcumin with Amlodipine in Hypertension.

Curcumin, a curcuminoid known as the main bioactive compound of turmeric, is used in foods, cosmetics, and pharmaceutical products. Amlodipine is a general antihypertensive drug used in combination with various other antihypertensive agents. To date, no studies have examined the effects of the co-administration of amlodipine with curcumin. In this study, the vasodilatory effects of curcumin, amlodipine, and the co-administration of curcumin with amlodipine on isolated rat aortic rings pre-contracted with phenylephrine were evaluated, and the hypotensive effects were evaluated using the tail cuff method. To measure blood pressure, male spontaneously hypertensive rats were divided into four groups, each containing six rats, as follows: amlodipine 1 mg/kg alone treated, amlodipine 1 mg/kg with curcumin 30 mg/kg treated, amlodipine 1 mg/kg with curcumin 100 mg/kg treated, and amlodipine 1 mg/kg with curcumin 300 mg/kg treated groups. Amlodipine and curcumin were intraperitoneally injected, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at 1, 2, 4, and 8 h after administration. The combined administration of curcumin and amlodipine induced a stronger vasorelaxant effect than amlodipine alone. However, co-administration did not significantly lower SBP and DBP compared to the single administration of amlodipine. The results of this study suggest that hypertensive patients taking amlodipine can consume curcumin or turmeric for food or other medical purposes without inhibiting the blood pressure-lowering effect of amlodipine.

Formulation development and in vitro characterization of triple layer tablet containing amlodipine besylate, rosuvastatin calcium and hydrochlorothiazide.

Triple layered tablet having various excipients and a new combination of APIs i.e. amlodipine besylate, rosuvastatin calcium and hydrochlorothiazide was prepared through wet granulation. The concentration of disintegrant and diluent was kept different in formulations of all APIs. At compression stage, nine different formulations from H1 to H9 having different combinations were prepared. Layers T1, T2 and T3 of all the three APIs had disintegrant concentration of 3%, 5% and 7 % respectively. In vitro analysis of granules was made by determining angle of repose, loss on drying, bulk density, tapped density, hausner ratio. Results of all these parameters were quite similar in all layers, which showed that change in disintegrant concentration does not affect the flow ability of granules to much extent. After compression, tablets were further subjected to weight variation, hardness, thickness, friability, disintegration, dissolution studies and FTIR. In vitro drug release data of all formulations were studied which showed that all the formulations exhibited zero order release. Results indicated that H8 had the best results in terms of physicochemical properties, assay and dissolution studies. The external morphology of formulations were further analyzed using scanning electron microscopy and differential scanning calorimetry. Triple layered tablet was successfully developed and characterized.

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design.

OBJECTIVES: In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS: One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine. CONCLUSION: This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment.

Preoperative Amlodipine Is Efficacious in Preventing Intraoperative HDI in Pheochromocytoma: Pilot RCT.

CONTEXT: Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce. OBJECTIVE: We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL. METHODS: In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure). RESULTS: The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ±â€…18.4% vs 2.44 ±â€…2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine). CONCLUSION: Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.

Adherence to triple-component antihypertensive regimens is higher with single-pill than equivalent two-pill regimens: A randomized controlled trial.

Using a single-pill combination (SPC) for hypertension (HTN) treatment resulted in better adherence and persistence than a free-equivalent combination in previous observational studies. The aim of this study is to confirm superior adherence with a triple-component SPC compared with an equivalent two-pill regimen in a randomized controlled trial (RCT) using a medication event monitoring system (MEMS). This is a multicenter, open-label, RCT. Subjects were persons with HTN whose clinic blood pressure was not adequately controlled (systolic >140 mmHg or diastolic >90 mmHg) with a dual combination. Eligible patients were randomized to either the triple-component SPC (olmesartan/amlodipine/hydrochlorothiazide 20/5/12.5 mg) group or the equivalent two-pill (olmesartan/hydrochlorothiazide 20/12.5 mg + amlodipine 5 mg) group and maintained for 12 weeks. Primary outcomes were the difference in percentage of doses taken (PDT) and percentage of days with the prescribed dose taken correctly (PDTc) between the single- and two-pill therapy groups, calculated from MEMS data. From 8 hospitals, 145 patients with HTN were randomized. The single-pill group had significantly higher PDT and PDTc than the two-pill group: median (25-75 percentile) PDT 95.1 (86.7-100.0) versus 92.1 (73.0-97.3); and PDTc 91.0 (79.4-96.5) versus 88.6 (69.2-96.3%), P = 0.04 for both by the Wilcoxon rank sum test. The single-pill combination of the triple-component antihypertensive regimen showed better adherence than the equivalent two-pill therapy. Reducing pill burden by means of a single-pill combination is an effective strategy for enhancing adherence to multiple-agent antihypertensive therapy. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Previous studies suggested that the use of a single-pill combination (SPC) in hypertension (HTN) treatment produced better adherence and persistence than a free-equivalent combination. However, supportive data are confined to dual-component SPC and came from observational studies using medication possession ratio as an outcome. WHAT QUESTION DID THIS STUDY ADDRESS? The objective of this study is to investigate whether a triple-component SPC improved medication adherence over an equivalent two-pill combination therapy in a randomized controlled trial using medication event monitoring systems. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Medication adherence in the SPC group was superior to that of two-pill group, confirming previous findings from observational studies. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This finding strongly supports the current HTN treatment guideline to prefer SPC with a higher level of evidence.

Safety of Candesartan, Amlodipine, and Atorvastatin in Combination: Interaction Study in Healthy Subjects.

For efficient cardiovascular risk protection antihypertensive treatment is often combined with cholesterol-lowering treatment, although solid data of interaction and side effects are missing. This is a prospective, single-center interaction study conducted in a fixed sequence design at steady state of candesartan, amlodipine, and atorvastatin. Five-day monotherapy of candesartan 8 mg was followed by 5-day atorvastatin 40 mg monotherapy and subsequently 9-day amlodipine 5 mg monotherapy; each treatment separated by washout phases. Immediately after amlodipine monotherapy, all 3 drugs were administered concomitantly for 5 days. Pharmacokinetic parameters as well as safety were assessed. Eighteen healthy subjects enrolled and completed the study. No significant difference in the maximum concentration (Cmax ) and the area the under plasma concentration-time curve (AUC) for amlodipine and AUC of atorvastatin was detected following combination versus monotherapy. Cmax of atorvastatin decreased slightly but clinically not relevantly when given in combination. A statistically significant but not below 0.80-fold decrease between candesartan following combination vs monotherapy was detected for Cmax and AUC. In general, all treatments were well tolerated. Concluding, systemic exposure of candesartan, amlodipine, and atorvastatin is not clinically significantly changed upon coadministration. These data support a fixed-dose combination of the 3 components for dual cardiovascular risk prevention.

Treatment effect of lacidipine and amlodipine on clinic and ambulatory blood pressure and arteria stiffness in a randomised double-blind trial.

PURPOSE: In a randomised, double-blind trial, we investigated effects of lacidipine on clinic and ambulatory blood pressure (BP) and arterial stiffness in patients with mild-to-moderate hypertension, as compared with amlodipine. MATERIALS AND METHODS: Previously untreated and treated patients (n = 269, 50-80 years of age) with clinic hypertension (a clinic systolic/diastolic BP 140-180/<110 mmHg and <160/100 mmHg, respectively) were randomly assigned to double-dummy treatment with lacidipine (4-6 mg/day) or amlodipine (5-7.5 mg/day) for 20 weeks. The primary efficacy variable was the change in 24-h ambulatory systolic BP at 20 weeks of treatment. Arterial stiffness was measured as brachial-ankle pulse wave velocity (PWV). RESULTS: After 20 weeks of treatment, 24-h systolic BP decreased from 141.3 ± 14.0 and 138.3 ± 12.8 mmHg at baseline, respectively, in the lacidipine (n = 134) and amlodipine groups (n = 135), by a least square mean (±SE) change of 15.2 ± 1.3 and 15.5 ± 1.3 mmHg, respectively, with a between-group difference (95% confidence interval [CI]) of 0.3 mmHg (-3.4 to 4.1, p = 0.86). Similar results were observed for other ambulatory BP components and clinic BP. Clinic and ambulatory pulse rate did not significantly change in either group (p ≥ 0.21). PWV decreased significantly (p < 0.001) from baseline in both groups, with a non-significant between-group difference of 0.24 m/s (p = 0.45). The incidence rate of adverse events was 30.3% (n = 40) and 27.5% (n = 36) in the lacidipine and amlodipine groups, respectively (p = 0.61). No serious adverse event occurred in the trial. CONCLUSIONS: Lacidipine effectively lowers clinic and ambulatory BP in patients with mild-to-moderate hypertension and significantly improves arterial stiffness, similarly as amlodipine.

Ultra-low-dose quadruple combination blood pressure-lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control, although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of 4 blood pressure-lowering agents each at a quarter dose may provide a simple, safe, and effective blood pressure-lowering solution which may also improve long-term adherence. The Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET) double-blind, active-controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline-recommended standard care in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or to control therapy of a single identical-appearing pill containing irbesartan 150 mg. In both arms, step-up therapy of open-label amlodipine 5 mg will be provided if blood pressure is >140/90 at 6 weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12-week follow-up. The primary outcome and some secondary outcomes will be assessed at 12 weeks; there is an optional 12-month extension phase to assess longer-term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects, and has better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure.